Corneal collagen cross‐linking for infectious keratitis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the comparative effectiveness and safety of CXL versus standard care for the treatment of infectious keratitis.
Background
Description of the condition
Infectious keratitis is an infection of the cornea that can be caused by bacteria, viruses, fungi, protozoa, or parasites (Bourcier 2003). It may be associated with ocular surgery, trauma, contact lens wear, or conditions that cause deficiency or loss of corneal sensation, or suppression of the immune system, such as diabetes, chronic use of topical steroids, or immunomodulatory therapies (Green 2008). The cornea is the clear curved surface that covers the front of the eye. It is composed of five layers. From outermost, they are the epithelium, Bowman's membrane, the stroma, Descemet’s membrane, and the endothelium. Infectious keratitis first affects the outermost epithelium and can progress to damage all five layers and perforate the cornea. Untreated infectious keratitis can lead to permanent visual impairment.
According to the Centers for Disease Control and Prevention (CDC), the overall burden and epidemiology of keratitis in the United States was estimated to include 930,000 doctor office and outpatient clinic visits and 58,000 emergency department visits annually; and 76.5% of keratitis visits resulted in antimicrobial prescriptions with an overall cost of about $175 million in direct health care expenditures, including $58 million for Medicare patients and $12 million for Medicaid patients, each year (Collier 2014). Outpatient clinic visits resulted in over 250,000 hours of clinician time annually.
Clinically, patients often present with a rapid onset of pain accompanied by conjunctival injection (red eye), photophobia (light sensitivity), and decreased vision. A corneal ulcer is an epithelial defect with surrounding and underlying inflammation caused by an influx of white blood cells. Generally, this results in necrosis of the surrounding tissue. For the purpose of this systematic review, the terms infectious keratitis and corneal ulcer are used interchangeably. Bacterial corneal ulcers display a sharp epithelial demarcation with underlying dense, suppurative stromal inflammation and edema (AAO 2013). Corneal ulcers typically are treated with topical antimicrobials/antibiotics; however, the widespread use of topical antibiotics may increase the incidence of multidrug‐resistant bacteria (Neu 1992). The high cost of developing new antimicrobial drugs and the rapid emergence of drug resistance make the development of alternative treatment approaches desirable (Bertino 2009; Wollensak 2006).
Description of the intervention
Collagen cross‐linking (CXL) of the cornea uses ultraviolet (UV)‐A rays in combination with riboflavin (vitamin B2 – a photosensitizer) to increase the biomechanical strength of the cornea and halt exacerbation of ectatic conditions of the cornea (Wollensak 2006). The resulting reaction involves reactive oxygen species and leads to stiffening/stabilization of the corneal stroma via the formation of cross‐links (covalent bonds) between the corneal stromal fibers (Wollensak 2003). Riboflavin has previously been shown to be activated by UV light to inactivate pathogens by damaging their RNA and DNA by oxidation (Goodrich 2000; Tsugita 1965).
How the intervention might work
A number of research studies have shown that CXL improves healing in microbial keratitis and blocks the progression of corneal melting (enzymatic degradation by bacteria) (Iseli 2008; Makdoumi 2010; Makdoumi 2012; Morén 2010). When activated by UV light, riboflavin induces a change in collagen properties, and has a hardening and strengthening effect on corneal stroma. As a result, a compromised cornea treated with activated riboflavin can become more resistant to corneal melting (Schilde 2008; Spoerl 2004). However, an intact cornea is protective in that it allows less than 10% of UV light to penetrate the eye. In individuals with corneal ulcers, there is greater penetration of UV light which could cause endothelial cell loss, consequently compromising the integrity of the cornea and corneal function and potentially resulting in decreased vision.
Why it is important to do this review
Observations have shown that corneal CXL could be a novel treatment for infectious keratitis. CXL has been shown to be effective in halting corneal melting, but the absence of control groups in past studies and previous reviews has meant that it has not been possible to confirm whether it is less, as, or more effective than antimicrobial treatments. To date, only one systematic review of CXL has been published, which included only one randomized controlled trial (RCT) (Alio 2013). Since this systematic review was published, however, several RCTs of CXL have been conducted. It is imperative to review and re‐evaluate these trials so that we can provide up‐to‐date information on which to base evidence‐based recommendations.
Objectives
To determine the comparative effectiveness and safety of CXL versus standard care for the treatment of infectious keratitis.
Methods
Criteria for considering studies for this review
Types of studies
We will include RCTs or quasi‐RCTs that have evaluated CXL for infectious keratitis. Inclusion of quasi‐RCTs will allow us to incorporate data from studies that assigned participants to treatment groups based on parameters such as date, day of the week/month, date of birth, identification number, etc. We will include quasi‐RCTs as we anticipate that few RCTs will be available for inclusion.
Types of participants
We will include studies that enrolled participants who had a diagnosis of infectious keratitis. When possible, we will document studies that enrolled participants with polymicrobial etiology (mixed infections) and cases involving bacterial, viral, fungal, protozoal, or parasitic infiltration, as well as cases with complications such as corneal perforations that warranted surgical intervention. We will exclude studies in which keratitis was not clearly diagnosed as having an infectious etiology.
Types of interventions
We will include studies comparing CXL with standard care for the management of infectious keratitis. Standard care typically includes topical antimicrobial or antibiotic treatments. Eligible studies will include those that examined CXL in combination with antimicrobial/antibiotic treatment versus standard care alone.
Types of outcome measures
Primary outcomes
The proportion of participants with re‐epithelization and complete healing with or without scar formation at four to eight weeks. Complete healing is defined as: absence of infiltrate, epithelial healing, and no sign of inflammation or epithelial defect.
Secondary outcomes
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Proportion of participants with best‐corrected visual acuity (BCVA) of 20/100 or better at four to eight weeks based on measurements made on a logMAR chart. We will analyze BCVA data from measurements made using any type of correction of refractive error (e.g. spectacles, rigid gas‐permeable contact lens). For participants whose premorbid BCVA was worse than 20/100, we will consider those who regained their premorbid BCVA.
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Mean change from baseline in BCVA at four to eight weeks, as measured on a logMAR chart.
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Proportion of participants with a reduction in corneal infiltrate, as defined by study investigators, at four to eight weeks.
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Proportion of participants with reduction in intraocular inflammation including, but not limited to, corneal keratic precipitates or anterior chamber cellular reaction at four to eight weeks.
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Proportion of participants with treatment failure, including, but not limited to, persistence or worsening of existing infectious keratitis, anterior chamber cellular reaction, corneal infiltrate, or epithelial defect, at four to eight weeks.
In the event that a trial reported an outcome for more than one time point within the range of four to eight weeks (e.g. at four weeks' and at six weeks' follow‐up), we will use the longest time point for analysis.
Adverse effects
We will document and compare the proportion of participants with adverse events at four to eight weeks in each group. Specific adverse events of interest include:
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increased infiltrate size;
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increased thinning or melting of the cornea, or need for corneal transplant;
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development or worsening of corneal edema;
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endophthalmitis;
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recurrence of corneal ulcer.
We will summarize and report other adverse effects related to CXL therapy reported in all included studies; however, it will be challenging to separate adverse outcomes of CXL from worsening infectious keratitis.
Search methods for identification of studies
Electronic searches
The Cochrane Eyes and Vision Information Specialist will search the following electronic databases. There will be no language or publication year restrictions.
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Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (latest issue) (Appendix 1);
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MEDLINE Ovid (1946 to present) (Appendix 2);
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Embase.com (1947 to present) (Appendix 3);
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PubMed (1948 to present) (Appendix 4);
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LILACS (Latin American and Caribbean Health Science Information database (1982 to present) (Appendix 5);
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov) (Appendix 6);
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp) (Appendix 7).
Searching other resources
We will search for additional eligible studies that have cited the trials included in this review using the Science Citation Index database. We will search the reference lists of included trials and previous review articles to find any other pertinent studies. We will not handsearch any journals or conference proceedings for this review.
Data collection and analysis
Selection of studies
Two review authors will independently review the titles and abstracts obtained from the literature searches and will classify each record according to relevancy to the inclusion criteria as "yes, relevant", "maybe", or "no, not relevant". We will use the web application, Covidence (Covidence), to manage the screening process. We will obtain full‐text reports of records classified as "yes" or "maybe" relevant. Two review authors will evaluate these full‐text reports and categorize them as "include", "awaiting assessment", or "exclude". If a study is categorized as awaiting assessment, we will contact the primary investigators to obtain more information and clarification. We will resolve all disagreements regarding the inclusion of a study through discussion at each stage of the screening process.
Data extraction and management
Two review authors will independently record data from study reports related to study methods, participants, interventions, and outcomes (Appendix 8). We will resolve disagreements or inconsistencies through discussion. We will contact the primary investigator of the study for information on missing data or to obtain clarification about unclear data. If we do not receive a response within two weeks, we will use the data as reported in the study reports. We will use forms developed by Cochrane Eyes and Vision, and administered by Covidence, to record data for individual studies. One review author will enter data into Review Manager 5 (RevMan 5) (Review Manager 2014); and a second review author will verify the data entry.
Assessment of risk of bias in included studies
Two review authors will independently examine each included study for risk of bias according to the methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will examine the studies for the following types of bias: (a) random sequence generation and allocation concealment before randomization (selection bias); (b) masking of study personnel (performance bias); (c) masking of outcome assessors (detection bias); (d) completeness of outcome data/follow‐up and intention‐to‐treat analysis (attrition bias); and (e) selective outcome reporting (reporting bias). Since masking of participants is uncommon, and often is impossible, in surgical studies, we will consider this a measure of risk of bias for the overall review rather than for individual studies.
Measures of treatment effect
We will evaluate the data according to the guidelines set out in Chapter 9 of theCochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). We will calculate mean differences with 95% confidence intervals for continuous outcomes, such as mean change in BCVA from baseline, and risk ratios with 95% confidence intervals for dichotomous outcomes, including the proportions of participants with re‐epithelialization and complete healing, a reduction in corneal infiltrate, a reduction in intraocular inflammation, treatment failure, and adverse effects.
Unit of analysis issues
We expect the unit of analysis for most included trials will be the individual (one study eye per participant). If outcomes for both participants' eyes have been reported in a study, we will document the trial design (e.g. within‐person or eyes as the unit of analysis) and how the trial investigators handled the data (e.g. used matched analysis for within‐person design or other analysis methods that took account of the non‐independence of eyes within the same person). When possible, we will obtain all outcome data and perform analyses that account properly for paired‐eye study designs in line with Chapter 9.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011).
Dealing with missing data
We will contact the primary investigators of the included trials to obtain any additional statistical information such as standard deviations or outcome data that are missing or not clearly reported. We will attempt to contact the primary investigators for a period of two weeks. If after this two‐week period additional data are not provided, we will use the data that are available in the available study report(s). We will not impute data for the purposes of this review.
Assessment of heterogeneity
If more than one study is included in the review, we will assess methodological and clinical heterogeneity by examining the study methods, population, interventions, and outcomes among trials. We will assess statistical heterogeneity among studies using the Chi² test and the I² statistic to estimate effect differences that are not due to chance. We will regard a P value from the Chi² test of less than 0.1 or an I² value of more than 50% to imply substantial statistical heterogeneity. We will evaluate forest plots for heterogeneity by examining the direction of effects and overlap of confidence intervals for effect estimates among the trials.
Assessment of reporting biases
When 10 or more studies are included in a meta‐analysis we will assess the symmetry of the funnel plot as a method to examine small‐study effects (Deeks 2011). We will assess the risk of selective outcome reporting as part of our assessment of risk of bias in the included studies.
Data synthesis
If data for one or more outcomes have been reported from multiple studies included in this review, meta‐analysis may be possible. In that case, we will combine the results of included trials when appropriate. If no clinical or methodological heterogeneity exists among the included studies, and no substantial statistical heterogeneity is identified, we will combine the data for each outcome in a meta‐analysis using a random‐effects model. If the number of included studies is fewer than three, we will use a fixed‐effect model. We will not combine trial results when significant statistical or clinical heterogeneity exists. Instead, we will provide a description and summarize the findings of each study.
Subgroup analysis and investigation of heterogeneity
When sufficient data are available, we will perform subgroup analyses based on type of infection (bacterial, viral, fungal, protozoal, or parasitic).
Sensitivity analysis
When sufficient data are available, we will perform sensitivity analyses to determine the consistency of effect estimates when excluding trials at high risk of bias, unpublished trials, and trials funded by industry.
Summary of findings
We will examine the overall certainty of evidence via the GRADE approach using the domains of risk of bias, imprecision, inconsistency, indirectness, and publication bias (Schünemann 2011). We will present our findings in a 'Summary of findings' table for the following outcomes.
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The proportion of participants with re‐epithelization and complete healing with or without scar formation at four to eight weeks.
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The proportion of participants with best‐corrected visual acuity (BCVA) of 20/100 or better at four to eight weeks. For participants whose premorbid BCVA was worse than 20/100, we will consider those who regained their premorbid BCVA.
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The proportion of participants with a reduction in corneal infiltrate at four to eight weeks.
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The proportion of participants with a reduction in intraocular inflammation at four to eight weeks.
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The proportion of participants with treatment failure at four to eight weeks.
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The proportion of participants with adverse events at four to eight weeks.
