The Orphan Drug for Acanthamoeba Keratitis (ODAK) Trial: PHMB 0.08% (Polihexanide) and Placebo versus PHMB 0.02% and Propamidine 0.1.

PURPOSE: To compare topical PHMB (polihexanide) 0.02% (0.2 mg/ml)+ propamidine 0.1% (1 mg/ml) with PHMB 0.08% (0.8 mg/ml)+ placebo (PHMB 0.08%) for Acanthamoeba keratitis (AK) treatment. DESIGN: Prospective, randomized, double-masked, active-controlled, multicenter phase 3 study (ClinicalTrials.gov identifier, NCT03274895). PARTICIPANTS: One hundred thirty-five patients treated at 6 European centers. METHODS: Principal inclusion criteria were 12 years of age or older and in vivo confocal microscopy with clinical findings consistent with AK. Also included were participants with concurrent bacterial keratitis who were using topical steroids and antiviral and antifungal drugs before randomization. Principal exclusion criteria were concurrent herpes or fungal keratitis and use of antiamebic therapy (AAT). Patients were randomized 1:1 using a computer-generated block size of 4. This was a superiority trial having a predefined noninferiority margin. The sample size of 130 participants gave approximately 80% power to detect 20-percentage point superiority for PHMB 0.08% for the primary outcome of the medical cure rate (MCR; without surgery or change of AAT) within 12 months, cure defined by clinical criteria 90 days after discontinuing anti-inflammatory agents and AAT. A prespecified multivariable analysis adjusted for baseline imbalances in risk factors affecting outcomes. MAIN OUTCOME MEASURES: The main outcome measure was MCR within 12 months, with secondary outcomes including best-corrected visual acuity and treatment failure rates. Safety outcomes included adverse event rates. RESULTS: One hundred thirty-five participants were randomized, providing 127 in the full-analysis subset (61 receiving PHMB 0.02%+ propamidine and 66 receiving PHMB 0.08%) and 134 in the safety analysis subset. The adjusted MCR within 12 months was 86.6% (unadjusted, 88.5%) for PHMB 0.02%+ propamidine and 86.7% (unadjusted, 84.9%) for PHMB 0.08%; the noninferiority requirement for PHMB 0.08% was met (adjusted difference, 0.1 percentage points; lower one-sided 95% confidence limit, -8.3 percentage points). Secondary outcomes were similar for both treatments and were not analyzed statistically: median best-corrected visual acuity of 20/20 and an overall treatment failure rate of 17 of 127 patients (13.4%), of whom 8 of 127 patients (6.3%) required therapeutic keratoplasty. No serious drug-related adverse events occurred. CONCLUSIONS: PHMB 0.08% monotherapy may be as effective (or at worse only 8 percentage points less effective) as dual therapy with PHMB 0.02%+ propamidine (a widely used therapy) with medical cure rates of more than 86%, when used with the trial treatment delivery protocol in populations with AK with similar disease severity. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Definition and Diagnostic Criteria for Pediatric Blepharokeratoconjunctivitis.

Importance: Pediatric blepharokeratoconjunctivitis (PBKC) is a chronic, sight-threatening inflammatory ocular surface disease. Due to the lack of unified terminology and diagnostic criteria, nonspecific symptoms and signs, and the challenge of differentiation from similar ocular surface disorders, PBKC may be frequently unrecognized or diagnosed late. Objective: To establish a consensus on the nomenclature, definition, and diagnostic criteria of PBKC. Design, Setting, and Participants: This quality improvement study used expert panel and agreement applying the non-RAND modified Delphi method and open discussions to identify unified nomenclature, definition, and definitive diagnostic criteria for PBKC. The study was conducted between September 1, 2021, and August 14, 2022. Consensus activities were carried out through electronic surveys via email and online virtual meetings. Results: Of 16 expert international panelists (pediatric ophthalmologists or cornea and external diseases specialists) chosen by specific inclusion criteria, including their contribution to scientific leadership and research in PBKC, 14 (87.5%) participated in the consensus. The name proposed was "pediatric blepharokeratoconjunctivitis," and the agreed-on definition was "Pediatric blepharokeratoconjunctivitis is a frequently underdiagnosed, sight-threatening, chronic, and recurrent inflammatory eyelid margin disease associated with ocular surface involvement affecting children and adolescents. Its clinical spectrum includes chronic blepharitis, meibomitis, conjunctivitis, and corneal involvement ranging from superficial punctate keratitis to corneal infiltrates with vascularization and scarring." The diagnostic criteria included 1 or more suggestive symptoms accompanied by clinical signs from 3 anatomical regions: the eyelid margin, conjunctiva, and cornea. For PBKC suspect, the same criteria were included except for corneal involvement. Conclusions and Relevance: The agreements on the name, definition, and proposed diagnostic criteria of PBKC may help ophthalmologists avoid diagnostic confusion and recognize the disease early to establish adequate therapy and avoid sight-threatening complications. The diagnostic criteria rely on published evidence, analysis of simulated clinical cases, and the expert panel's clinical experience, requiring further validation with real patient data analysis.

Acanthamoeba Keratitis Risk Factors for Daily Wear Contact Lens Users: A Case-Control Study.

PURPOSE: This study was designed to establish risk factors for the development of Acanthamoeba keratitis (AK) for daily disposable (DD) contact lens (CL) users compared with daily wear (DW) reusable lens users and for risks unique to DD users. This is important because, in many major economies, CL use is the principal cause of microbial keratitis, of which AK accounts for approximately 50% of cases with sight loss. Determining these AK risks informs practitioner advice and consumer behavior. DESIGN: Case-control study. PARTICIPANTS: Cases and controls were recruited from an Accident and Emergency Department serving South-East England. Cases were new CL users with AK recruited retrospectively from January 2011 to February 2013 and prospectively thereafter until August 2014. Controls were recruited prospectively from February 2014 to June 2015. METHODS: Analysis of a self-administered questionnaire. MAIN OUTCOME MEASURES: Independent risk factors and population attributable risk percentage (PAR%) for AK. RESULTS: A total of 83 AK cases and 122 controls were recruited; DD use was reported by 20 (24%) cases and 66 (54%) controls. In multivariable analyses adjusted for potential confounders, the odds of AK was higher for DW reusable soft lenses (odds ratio [OR], 3.84; 95% confidence interval [CI], 1.75-8.43) and rigid lenses (OR, 4.56; 95% CI, 1.03-20.19) than for DD lenses. Within the DD-using subset, AK was associated with the following modifiable risk factors: less frequent professional follow-up visits (OR, 10.12; 95% CI, 5.01-20.46); showering in lenses (OR, 3.29, 95% CI, 1.17-9.23); lens reuse (OR, 5.41; 95% CI, 1.55-18.89); and overnight wear (OR, 3.93; 95% CI, 1.15-13.46). The PAR% estimated that 30% to 62% of cases could be prevented by switching from reusable soft lens to DD lens use. CONCLUSIONS: Acanthamoeba keratitis risks are increased > threefold in DW reusable lens users versus DD lens use. Acanthamoeba keratitis risks for DD lens users can be minimized by adherence to safe use guidelines (no reuse, overnight wear, or contamination by water). Safe CL use can be improved by increasing the prominence of risk avoidance information from manufacturers and regulators. Because AK accounts for half of severe keratitis in CL users, these measures can be expected to have public health benefits.

Safety and tolerability of topical polyhexamethylene biguanide: a randomised clinical trial in healthy adult volunteers.

BACKGROUND AND AIMS: Polyhexamethyl biguanide (PHMB), a widely used topical treatment for Acanthamoeba keratitis (AK), is unlicensed with no formal safety assessment. This study evaluated its safety and tolerability. METHODS: A prospective, randomised, double-masked controlled trial in 90 healthy volunteers. Subjects were treated with topical 0.04%, 0.06%, 0.08% PHMB or placebo (vehicle) 12× daily for 7 days, then 6× daily for 7 days. The rates of dose-limiting adverse events (DLAEs) leading to interruption of dosing, mild adverse events (AEs) (not dose limiting) and incidental AEs (unrelated to treatment) were compared. The primary outcome was the difference between treatments for DLAE rates. RESULTS: 5/90 subjects developed DLAE within <1-4 days of starting treatment; 2/5 using PHMB 0.06% and 3/5 PHMB 0.08%. These resolved within 1-15 days. There were no significant differences in DLAE between treatment groups. Mild AEs occurred in 48/90 subjects (including placebo). There was no trend for an increased incidence of any AE with increasing concentrations of PHMB, except for corneal punctate keratopathy with PHMB 0.08%, which fully resolved within 7-14 days. CONCLUSION: These findings are reassuring for PHMB 0.02% users. They also suggest that higher PHMB concentrations may show acceptable levels of tolerance and toxicity in AK subjects, whose susceptibility to AE may be greater than for the normal eyes in this study. Given the potential benefits of higher PHMB concentrations for treating deep stromal invasion in AK, we think that the use of PHMB 0.08% is justified in treatment trials. TRIAL REGISTRATION NUMBER: NCT02506257.

Comparison of culture, confocal microscopy and PCR in routine hospital use for microbial keratitis diagnosis.

AIMS: To evaluate the sensitivity and specificity of polymerase chain reaction (PCR), in vivo confocal microscopy (IVCM) and culture for microbial keratitis (MK) diagnosis. METHODS: Retrospective review of PCR, IVCM and culture results for MK diagnosis at Moorfields Eye Hospital between August 2013 and December 2014. RESULTS: PCR results were available for 259 MK patients with concurrent culture for 203/259 and IVCM for 149/259. Sensitivities and specificities with 95% confidence intervals [95% CI] were calculated for Acanthamoeba keratitis (AK) and fungal keratitis (FK), by comparison with culture, for both IVCM and PCR. For AK, FK and bacterial keratitis (BK) sensitivities were calculated, for each diagnostic method, by comparison with a composite reference standard (a positive result for one or more of culture, PCR or IVCM having a specificity of 100% by definition). For the latter, sensitivities with [95% CI] were: for AK, IVCM 77.1% [62.7-88.0%], PCR 63.3% [48.3-76.6%], culture 35.6 [21.9-51.2]; for FK, IVCM 81.8% [48.2-97.7%], PCR 30.8% [9.09-61.4%], culture 41.7% [15.2-72.3%]; for BK, PCR 25.0% [14.7-37.9%], culture 95.6% [87.6-99.1%]. CONCLUSION: IVCM was the most sensitive technique for AK and FK diagnosis but culture remains our gold standard for BK. These findings reflect results to be expected from service providers to UK ophthalmology units and demonstrates the need at our centre for ongoing diagnostic result audit leading to the potential to improve PCR diagnosis. Both FK and AK are now common in the UK; ophthalmology units need to have all these techniques available to optimise their MK management.

Acanthamoeba keratitis therapy: time to cure and visual outcome analysis for different antiamoebic therapies in 227 cases.

AIMS: To test the hypothesis that Acanthamoeba keratitis (AK) outcomes differ for different topical antiamoebic therapies (AAT) and to provide the detailed patient outcome data. METHODS: A retrospective cohort study of 227 patients developing AK between 25 July 1991 and 10 August 2012. Inclusion criteria required a complete record of AAT treatment for both the primary outcome of a medical cure rate at 12 months and the secondary outcome of Snellen visual acuity ≤6/24 and/or surgical intervention. Analysis used multivariable regression to control for differences in baseline disease characteristics for both primary and secondary outcomes with unadjusted analyses for other outcomes. Subjects were categorised for analysis both by the AAT used at baseline and also by mutually exclusive AAT (patients exposed to all the drugs in each group, and no others, for some period). AAT categories were PHMB monotherapy, PHMB+diamidine, PHMB+chlorhexidine+diamidine, diamidine monotherapy and other AAT. RESULTS: Analysis by baseline AAT showed no notable difference between treatments for both a medical cure at 12 months in 60.79% (138/227) or for a poor outcome in 49.34% (112/227). When AATs were analysed by mutually exclusive groups, PHMB monotherapy provided the best outcomes. These findings are subject to bias requiring careful interpretation. Overall cure rates for the 214 subjects with resolved outcomes were 94.27% (214/227), median time to cure 5 months (IQR 3.25-9.00 months) and range 1-26.24 months. CONCLUSION: PHMB 0.02% monotherapy for the initial treatment of AK is as effective as biguanide+diamidine combination therapy. Chlorhexidine monotherapy was too infrequent for comparison. The outcome data are the most detailed available.

Acanthamoeba keratitis: confirmation of the UK outbreak and a prospective case-control study identifying contributing risk factors.

BACKGROUND/AIMS: Acanthamoeba keratitis (AK) is a chronic debilitating corneal infection principally affecting contact lens (CL) users. Studies were designed to test claims that the UK incidence may have increased in 2012-2014 and to evaluate potential causes. METHODS: Annualised incidence data were collected from January 1984 to December 2016. Case-control study subjects were recruited between 14 April 2011 and 05 June 2017. Reusable CL users with AK were recruited retrospectively and prospectively. Controls were reusable CL users, recruited prospectively, with any disorder other than AK. Multivariable analysis of questionnaire data measured independent risk factors for AK. RESULTS: The current outbreak of AK started in 2010-2011 with an incidence threefold higher than in 2004-2009. Risk factors for AK were: Oxipol disinfection, CLs made of group IV CL materials, poor CL hygiene, deficient hand hygiene, use of CLs while swimming or bathing, being white British, and for those in social classes 4-9. CONCLUSION: AK is a largely preventable disease. The current outbreak is unlikely to be due to any one of the identified risk factors in isolation. Improving CL and hand hygiene, avoiding CLs contamination with water and use of effective CL disinfection solutions, or daily disposable CLs, will reduce the incidence of AK. In the longer-term, water avoidance publicity for CL users can be expected to reduce the incidence further. Ongoing surveillance of AK numbers will identify changes in incidence earlier. Evaluation of Acanthamoeba contamination in end-user drinking water would contribute to our understanding of regional variations in the risk of exposure.

Acanthamoeba keratitis in 194 patients: risk factors for bad outcomes and severe inflammatory complications.

BACKGROUND/AIMS: To determine demographic and clinical features of patients with Acanthamoeba keratitis (AK) that are independent risk factors both for bad outcomes and for severe inflammatory complications (SIC). METHODS: A retrospective audit of medical records of AK cases at Moorfields Eye Hospital from July 2000 to April 2012, including 12 earlier surgical cases. Cases with a bad outcome were defined as those having one or more of the following: corneal perforation, keratoplasty, other surgery (except biopsy), duration of antiamoebic therapy (AAT) ≥10.5 months (the 75th percentile of the whole cohort) and final visual acuity ≤20/80. SICs were defined as having scleritis and/or a stromal ring infiltrate. Multivariable analysis was used to identify independent risk factors for both bad outcomes and SICs. RESULTS: Records of 194 eyes (194 patients) were included, having bad outcomes in 93 (48%). Bad outcomes were associated with the presence of SIC, aged >34 years, corticosteroids used before giving AAT and symptom duration >37 days before AAT. The development of SIC was independently associated with aged >34 years, corticosteroids used before giving AAT and herpes simplex virus (HSV) keratitis treatment before AAT. CONCLUSIONS: The prompt diagnosis of AK, avoidance of a misdiagnosis of HSV keratitis and corticosteroid use before the exclusion of AK as a potential cause of keratitis are essential to the provision of a good outcome for patients and for the avoidance of SIC. Older age is an unmodifiable risk factor that may reflect differences in the immune response to AK in this patient subset.

Altered Patterns of Fungal Keratitis at a London Ophthalmic Referral Hospital: An Eight-Year Retrospective Observational Study.

PURPOSE: In previous studies of fungal keratitis (FK) from temperate countries, yeasts were the predominant isolates, with ocular surface disease (OSD) being the leading risk factor. Since the 2005-2006 outbreak of contact lens (CL)-associated Fusarium keratitis, there may have been a rise in CL-associated filamentary FK in the United Kingdom. This retrospective case series investigated the patterns of FK from 2007 to 2014. We compared these to 1994-2006 data from the same hospital. DESIGN: Retrospective observational study. METHODS: All cases of FK presenting to Moorfields Eye Hospital between 2007 and 2014 were identified. The definition of FK was either a fungal organism isolated by culture or fungal structures identified by light microscopy (LM) of scrape material, histopathology, or in vivo corneal confocal microscopy (IVCM). Main outcome measure was cases of FK per year. RESULTS: A total of 112 patients had confirmed FK. Median age was 47.2 years. Between 2007 and 2014, there was an increase in annual numbers of FK (Poisson regression, P = .0001). FK was confirmed using various modalities: 79 (70.5%) by positive culture, 16 (14.3%) by LM, and 61 (54.5%) by IVCM. Seventy-eight patients (69.6%) were diagnosed with filamentary fungus alone, 28 (25%) with yeast alone, and 6 (5.4%) with mixed filamentary and yeast infections. This represents an increase in the proportion of filamentary fungal infections from the pre-2007 data. Filamentary fungal and yeast infections were associated with CL use and OSD, respectively. CONCLUSIONS: The number of FK cases has increased. This increase is due to CL-associated filamentary FK. Clinicians should be aware of these changes, which warrant epidemiologic investigations to identify modifiable risk factors.

The Impact of Topical Corticosteroids Used in Conjunction with Antiamoebic Therapy on the Outcome of Acanthamoeba Keratitis.

PURPOSE: To examine the impact of topical corticosteroid use after the start of antiamoebic therapy (AAT) on the outcomes of Acanthamoeba keratitis (AK) therapy. DESIGN: Cohort study. PARTICIPANTS: A total of 196 patients diagnosed with AK at Moorfields Eye Hospital, London, between January 1991 and April 2012. In 13 patients with bilateral AK, 1 eye was randomly excluded from analysis. METHODS: Patient demographics and clinical examination findings were collected both at the start of AAT and subsequently at the time that topical corticosteroid therapy was initiated. Preliminary a priori investigations were used to identify effect modifiers/confounders and extreme associations requiring consideration in multivariate regression modeling. A multivariable logistic model, optimized for assessment of corticosteroid use after the start of AAT, was used to estimate the odds ratios (ORs) of a suboptimal outcome. MAIN OUTCOME MEASURES: Suboptimal outcome was defined as final visual acuity ≤20/80, corneal perforation, or the need for keratoplasty. RESULTS: In multivariable analysis, restricted to 129 eyes (1 eye per patient) free of scleritis and hypopyon at the start of AAT, topical corticosteroids were not associated with worse outcomes (OR, 1.08; 95% confidence interval [CI], 0.39-3.03), even when corticosteroids had been used before the start of AAT. Risk factors significantly associated with worse outcomes were topical corticosteroid use before the start of AAT (OR, 3.85; 95% CI, 1.35-11.03), a corneal ring infiltrate (together with at least 1 other feature of AK) present at the start of AAT (OR, 5.89; 95% CI, 1.17-29.67), and age ≥33 years at the start of AAT (OR, 4.02; 95% CI, 1.46-11.06). CONCLUSIONS: Many corneal specialists currently are uncertain about the risk benefit associated with the use of topical corticosteroids for the management of inflammatory complications of AK. The evidence from this study gives clinicians and patients reassurance that the potential benefits of topical corticosteroid therapy, for treating pain and discomfort, are not associated with worse outcomes when initiated after starting modern AAT. Other potential benefits, in terms of resolution of inflammatory complications, will not be demonstrated without a carefully designed randomized clinical trial.

Therapeutic and optical keratoplasty in the management of Acanthamoeba keratitis: risk factors, outcomes, and summary of the literature.

OBJECTIVE: To report the risk factors for and outcomes of therapeutic and optical keratoplasty in the management of Acanthamoeba keratitis (AK). DESIGN: Retrospective case series. PARTICIPANTS: A total of 50 eyes of 196 patients with retrievable medical records, diagnosed with AK at Moorfields Eye Hospital, London, underwent keratoplasty between January 1991 and April 2012. METHODS: Patient demographics, initial clinical examination findings, and management details were collected. The ophthalmic characteristics of patients who underwent keratoplasty for AK were compared with those who did not. Patients undergoing therapeutic keratoplasty were compared with those undergoing optical keratoplasty for baseline characteristics, management details, and visual outcomes. A multivariate logistic model was used to derive the odds ratios of a poor visual outcome in all keratoplasty patients. MAIN OUTCOME MEASURES: Poor visual outcome was defined as final visual acuity of 20/200 or worse. Secondary outcomes of interest included number of clinic visits and the need for additional intraocular surgery. RESULTS: Of the 196 AK patients, a total of 50 patients (25.5%) underwent penetrating or anterior lamellar keratoplasty, 10 of whom (20%) underwent repeat procedures. Of these 50 patients, 26 (52%) had therapeutic keratoplasty, predominantly for corneal perforation. The remaining 24 patients (48%) underwent optical keratoplasty for visual rehabilitation. Thirty-seven (80.4%) patients in the keratoplasty group initially were misdiagnosed as having herpes simplex keratitis versus 59 (41.8%) patients who did not require a keratoplasty (P < 0.001). Final visual outcomes were significantly better in the optical group compared with the therapeutic group, with 13 (54.2%) achieving visual acuity of 20/30 or better versus 7 (26.9%), respectively. On multivariate analysis, beginning therapy at a hospital other than Moorfields and undergoing a therapeutic, rather than an optical, keratoplasty were associated significantly with a poor visual outcome from keratoplasty. CONCLUSIONS: The prognosis of keratoplasty differs markedly when performed for therapeutic purposes compared with visual rehabilitation. Where possible, keratoplasty should be delayed until such time as the eye is uninflamed and medically cured of Acanthamoeba.

The impact of topical corticosteroid use before diagnosis on the outcome of Acanthamoeba keratitis.

OBJECTIVE: To examine the impact of topical corticosteroid use before the diagnosis of Acanthamoeba keratitis (AK) on final visual outcomes and to determine the prognostic factors predicting poorer outcomes. DESIGN: Cohort study. PARTICIPANTS: A total of 209 eyes of 196 patients with retrievable medical records, diagnosed with AK at Moorfields Eye Hospital, London, between January 1991 and April 2012. One eye was randomly excluded from analysis in the 13 cases of bilateral AK. METHODS: Patient demographic, initial clinical examination findings, and management details were collected. The outcomes of patients treated with topical corticosteroids before diagnosis of AK were compared with those not treated with topical corticosteroids before diagnosis. A multivariable logistic model, optimized for prior corticosteroid use, was used to derive the odds ratios (ORs) of a suboptimal visual outcome. MAIN OUTCOME MEASURES: Suboptimal visual outcome was defined as final visual acuity (VA) ≤ 20/80, corneal perforation, or need for keratoplasty. RESULTS: Acanthamoeba keratitis was diagnosed on microbiological culture in 94 eyes (48.0%), on histopathologic examination in 27 eyes (13.8%), on confocal microscopy in 38 eyes (19.4%), and on the basis of a typical clinical course and response to treatment in 37 eyes (18.9%). Final VA and prior corticosteroid use data were available for 174 eyes (88.8%). In multivariable analysis, corticosteroid use before diagnosis was associated with suboptimal visual outcome (OR, 3.90; 95% confidence interval [CI], 1.78-8.55), as were disease stage 3 at presentation (OR, 5.62; 95% CI, 1.59-19.80) and older age (60+ years) at diagnosis (OR, 8.97; 95% CI, 2.13-37.79). CONCLUSIONS: Corticosteroid use before diagnosis of AK is highly predictive of a poorer visual outcome. This is largely due to the initial misdiagnosis of AK as herpetic keratitis. It is important to include AK in the differential diagnosis of keratitis in all contact lens users with keratitis, particularly before making a diagnosis of herpes keratitis and before the use of topical corticosteroids in the therapy of any indolent keratitis.

Subconjunctival bevacizumab induces regression of corneal neovascularisation: a pilot randomised placebo-controlled double-masked trial.

OBJECTIVE: To evaluate the off-label use of subconjunctival bevacizumab for corneal neovascularisation (CoNV). METHODS: 30 patients with recent-onset CoNV from various causes were randomly assigned into a double-masked, placebo-controlled trial. Each received three 0.1 ml injections containing either 2.5 mg bevacizumab or 0.9% saline at monthly intervals. Dexamethasone 0.1% drops were used four times a day for the first month, when the dose was modified if clinically indicated. The primary outcome was change in area of corneal involvement by CoNV from baseline to 3 months measured using specialised imaging technology. RESULTS: The mean area of CoNV reduced by -36% (range -92% to +40%) in the 15 eyes that received bevacizumab compared with an increase of 90% (range -58% to +1394%) in eyes that received saline placebo (analysis of covariance (ANCOVA); p=0.007). One outlier in the placebo arm developed corneal graft rejection with aggressive neovascularisation (+1384%), but even when this patient was excluded the mean reduction in CoNV in the placebo group (-3%, range -58% to +40%) was still significantly different from the treatment arm (ANCOVA; p=0.016). Changes in best-corrected visual acuity, central corneal thickness, intraocular pressure and endothelial cell counts were similar between groups. The intervention was well tolerated with no major safety concerns. CONCLUSIONS: Three subconjunctival injections of 2.5 mg bevacizumab are more effective than placebo at inducing the regression of recent-onset CoNV. Further studies are needed to confirm this effect and our data suggest that a sample size of 40 patients per treatment group is required.

Immune defense single nucleotide polymorphisms and recruitment strategies associated with contact lens keratitis.

PURPOSE: To determine the association of single nucleotide polymorphisms (SNPs) of defensin 1B and toll-like receptor 4 with contact lens keratitis susceptibility and severity, and to understand the factors that influence study participation. DESIGN: Retrospective, case-control study. PARTICIPANTS: Ninety cases of keratitis and 185 controls recruited from studies conducted at Moorfields Eye Hospital and throughout Australia from 2003 to 2005 were analyzed for genetic associations. The reasons for participation of a subset of 146 participants from 1 site were also investigated. METHODS: Buccal swab samples were collected on Whatman FTA cards and mailed by post for analysis. DEFB1 (rs1799946, -52, rs1800972, -44, and rs11362, -20) and TLR4 (rs4986790, D299G) SNPs were screened by pyrosequencing and analyzed using a regression model for susceptibility (sterile, microbial keratitis [MK], controls) and severity. Study participation was investigated for age, gender, condition, and phone follow-up also using regression analysis. MAIN OUTCOME MEASURES: Relative risk of developing contact lens-related keratitis and more severe forms of the disease based on genetic profiles. RESULTS: Carriers of risk alleles of DEFB1 -52 and -20 showed a trend toward increased susceptibility to keratitis (-52: odds ratio [OR], 1.45; 95% confidence interval [CI], 0.99-2.11; P = 0.051; -20: OR, 1.37; 95% CI, 0.95-1.98; P = 0.088). A DEFB1 promoter haplotype (G-G-A) had a tendency toward decreased susceptibility of MK (OR, 0.68; 95% CI, 0.45-1.03; P = 0.062) and reduced severity (OR, 0.56; 95% CI, 0.30-1.07; P = 0.066). The TLR4 D299G was not associated with type and severity of keratitis. Older age (OR, 1.07; 95% CI, 1.05-1.08) and follow-up phone call (OR, 2.0; 95% CI, 1.2-3.5) were independent predictors of study participation. CONCLUSIONS: Genetic variation in DEFB1 that may lead to decreased protein expression of hBD-1 exhibits a tendency toward increased susceptibility and severity of contact lens-related keratitis. Investigation of these and other hBD genes that play important roles in animal models in a larger sample size is warranted. The approach of requesting samples from retrospective case series was generally feasible, although significant resources, including repeat phone calls, are required. More targeted strategies to recruit younger individuals to participate in genetic studies may be useful.

Corneal transplantation.

Corneal transplantation or keratoplasty has developed rapidly in the past 10 years. Penetrating keratoplasty, a procedure consisting of full-thickness replacement of the cornea, has been the dominant procedure for more than half a century, and successfully caters to most causes of corneal blindness. The adoption by specialist surgeons of newer forms of lamellar transplantation surgery, which selectively replace only diseased layers of the cornea, has been a fundamental change in recent years. Deep anterior lamellar keratoplasty is replacing penetrating keratoplasty for disorders affecting the corneal stromal layers, while eliminating the risk of endothelial rejection. Endothelial keratoplasty, which selectively replaces the corneal endothelium in patients with endothelial disease, has resulted in more rapid and predictable visual outcomes. Other emerging therapies are ocular surface reconstruction and artificial cornea (keratoprosthesis) surgery, which have become more widely available because of rapid advances in these techniques. Collectively, these advances have resulted in improved outcomes, and have expanded the number of cases of corneal blindness, which can now be treated successfully. Femtosecond-laser-assisted surgery, bioengineered corneas, and medical treatment for endothelial disease are also likely to play a part in the future.

Association of single nucleotide polymorphisms of interleukins-1ß, -6, and -12B with contact lens keratitis susceptibility and severity.

PURPOSE: To investigate whether single nucleotide polymorphisms (SNPs) in interleukin (IL)-1ß, IL-6, and IL-12ß are associated with the susceptibility and severity of contact lens-related keratitis. DESIGN: Retrospective, case control study. PARTICIPANTS: One hundred twelve cases of keratitis and 225 controls were recruited from studies conducted at Moorfields Eye Hospital and in Australia during 2003 through 2005. METHODS: Buccal swab samples were collected on Whatman FTA cards and were mailed by post for analysis. IL-1ß (-31), IL-6 (-174, -572, -597), and IL-12B (3'+1158) genotypes were analyzed with pyrosequencing and analyzed using a regression model for susceptibility (sterile, microbial keratitis, controls) and severity. Statistical significance was set at 0.05. MAIN OUTCOME MEASURES: The relative risk of developing contact lens-related keratitis and more severe forms of the disease based on allele, genotype, and haplotype associations. RESULTS: Carriers of IL-6 SNPs were more likely to experience moderate and severe events compared with those with nonmutated genotypes (-174 heterozygous: odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-8.3; homozygous: OR, 6.4; 95% CI, 1.4-28.4; -174/-597: OR, 4.1; 95% CI, 1.6-11.0). More severe keratitis and microbial keratitis were less likely to occur in wearers with the nonmutated IL-6 haplotype (severity OR, 0.4 [95% CI, 0.2-0.7]; microbial OR, 0.6 [95% CI, 0.4-0.9]). Wearers carrying an IL-12B SNP had an increased risk of sterile keratitis (OR, 9.7; 95% CI, 1.2-76.9) compared with controls. CONCLUSIONS: The IL-6 SNPs are known to reduce protein expression of this cytokine and thus ocular immune defense, and carriers of these SNPs were more likely to experience more severe and microbial keratitis, suggesting that IL-6 decreases the severity and susceptibility of contact lens-related keratitis. Carriers of a functional SNP of IL-12B that is known to increase IL-12 expression and stability are more likely to experience sterile keratitis, suggesting that this is associated with the intense inflammatory reaction that occurs in this condition.

Risk factors for moderate and severe microbial keratitis in daily wear contact lens users.

OBJECTIVE: To establish risk factors for moderate and severe microbial keratitis among daily contact lens (CL) wearers in Australia. DESIGN: A prospective, 12-month, population-based, case-control study. PARTICIPANTS: New cases of moderate and severe microbial keratitis in daily wear CL users presenting in Australia over a 12-month period were identified through surveillance of all ophthalmic practitioners. Case detection was augmented by record audits at major ophthalmic centers. Controls were users of daily wear CLs in the community identified using a national telephone survey. TESTING: Cases and controls were interviewed by telephone to determine subject demographics and CL wear history. Multiple binary logistic regression was used to determine independent risk factors and univariate population attributable risk percentage (PAR%) was estimated for each risk factor. MAIN OUTCOME MEASURES: Independent risk factors, relative risk (with 95% confidence intervals [CIs]), and PAR%. RESULTS: There were 90 eligible moderate and severe cases related to daily wear of CLs reported during the study period. We identified 1090 community controls using daily wear CLs. Independent risk factors for moderate and severe keratitis while adjusting for age, gender, and lens material type included poor storage case hygiene 6.4× (95% CI, 1.9-21.8; PAR, 49%), infrequent storage case replacement 5.4× (95% CI, 1.5-18.9; PAR, 27%), solution type 7.2× (95% CI, 2.3-22.5; PAR, 35%), occasional overnight lens use (<1 night per week) 6.5× (95% CI, 1.3-31.7; PAR, 23%), high socioeconomic status 4.1× (95% CI, 1.2-14.4; PAR, 31%), and smoking 3.7× (95% CI, 1.1-12.8; PAR, 31%). CONCLUSIONS: Moderate and severe microbial keratitis associated with daily use of CLs was independently associated with factors likely to cause contamination of CL storage cases (frequency of storage case replacement, hygiene, and solution type). Other factors included occasional overnight use of CLs, smoking, and socioeconomic class. Disease load may be considerably reduced by attention to modifiable risk factors related to CL storage case practice.