Purpose
To summarize key findings from a Cochrane systematic review of the effectiveness and safety of topical pharmacologic interventions compared with active control or placebo for epidemic keratoconjunctivitis (EKC).
Design
Systematic review.
Methods
We included randomized controlled trials that compared antiseptic agents, virustatic agents, or immune-modulating topical therapies with placebo or an active control. We adhered to Cochrane methods for trial selection, data extraction, risk of bias evaluation, and data synthesis.
Results
Ten randomized controlled trials with 892 participants with acute or chronic EKC were included. Eight trials compared interventions with artificial tears or saline (n = 4) or with steroids (n = 4); two 3-arm trials contributed data to both comparisons. Estimates suggested that compared with tears, after povidone-iodine (PVP-I) alone (2 studies, 409 participants) more participants with acute EKC had resolution of symptoms (risk ratio [RR] 1.15 [95% confidence interval {CI} 1.07-1.24]) and signs (RR 3.19 [95% CI 2.29-4.45]) within 10 days. In 2 trials comparing treatments with steroid alone or steroid with levofloxacin, fewer eyes treated with PVP-I or polyvinyl alcohol iodine (PVA-I) plus steroid developed subepithelial infiltrates within 21 days (RR 0.08 [95% CI 0.01-0.55]; 69 eyes). No treatment was shown to improve resolution of infiltrates.
Conclusions
Low- to very low–level certainty of evidence suggested that PVP-I or PVA-I with steroid may confer some benefit in acute EKC, but imprecision from small sample sizes, the potential risk of bias from inadequate reporting or trial design, and variability in participant selection, outcome measurement, and reporting limit the amount and quality of evidence.
V iruses cause about 80% of all cases of acute conjunctivitis. Human adenoviruses (HAdVs) are believed to account for 65% to 90% of cases of viral conjunctivitis, or 20% to 75% of all causes of infectious keratoconjunctivitis (KC) worldwide, making them the most common cause of viral conjunctivitis. , , Epidemic KC (EKC) is a highly infectious subset of conjunctivitis caused by HAdVs and, to a much lesser extent, by Coxsackievirus and Enterovirus. Large outbreaks of adenoviral EKC have occurred on military installations and at medical centers. In a 6-month period in Chicago, 401 patients, staff members, and physicians at the Illinois Eye and Ear Infirmary developed adenoviral EKC. EKC is accompanied by severe conjunctival inflammation, watery discharge, and light sensitivity and can lead to chronic complications, such as scarring from corneal subepithelial infiltrates (SEIs), conjunctival membranes, symblepharon, , and dry eye syndrome. SEI can develop a few weeks after the acute phase of EKC and often is associated with long-term symptoms of glare and impaired quality of vision.
There is lack of consensus on the efficacy of any treatment to alter the clinical course of EKC, which has at least 2 distinct clinical and pathophysiological phases: the acute phase, in which viral replication and ocular surface inflammation are prominent, and the chronic, or delayed phase, which manifests later and is clinically evident solely as corneal SEIs. Many clinicians offer only supportive care in the form of lubrication and cold compresses to provide symptom relief during the acute phase. The goals of pharmacotherapy for either phase are to lessen symptom severity, to shorten the duration of signs and symptoms, to restore comfort and visual function, and, for the acute phase, to decrease development of sequelae (eg, SEIs, membranes, symblepharon) associated with long-term morbidity. Successful treatment must be balanced against long-term dependence on or adverse effects from pharmacotherapy. Although not a commonly reported outcome measure, an important goal of therapy is prevention of transmission of EKC to an unaffected fellow eye.
Some clinicians offer topical corticosteroids for highly symptomatic patients, especially those with SEIs or membranes. Other treatments have included virustatic agents, such as cidofovir and cyclosporine A (CsA), , interferon B, and tacrolimus. It is unclear whether these therapies are more effective than no treatment or artificial tears. Treatment typically costs more than vehicle, artificial tears, or no treatment and may induce drug allergy, sensitivity, or toxicity to the eye or prolong viral shedding. , However, rapid resolution of signs and symptoms restores vision-related quality of life and ability to return to work. The main objective of this summary of our Cochrane systematic review is to report the comparative safety and effectiveness of topical pharmacologic interventions compared with placebo, active control, or no treatment, based on the best currently available evidence.
METHODS
Adhering to the methods in the Cochrane Handbook for Systematic Reviews of Interventions , we included randomized controlled trials (RCTs) in our review. A summary of methods is provided below; details can be found in the full Cochrane systematic review. Eligible trials compared antiviral agents (ganciclovir and trifluridine), corticosteroids, antiseptic agent (PVP-I or equivalent), calcineurin inhibitors (CsA and tacrolimus), without regard for dosage or duration of treatment, with control interventions. Control treatments included placebo, vehicle, artificial tears, saline, no treatment, or corticosteroids. We excluded studies of participants with adenoviral conjunctivitis that was not specified as EKC unless there was an EKC subgroup that had been randomized and for which outcomes had been reported separately. In our search, we included trials that enrolled patients in any phase of EKC. We included studies that enrolled both adult and pediatric patients.
SEARCH METHODS
We searched the electronic databases CENTRAL (which contains the Cochrane Eyes and Vision Trials Register), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, EMBASE, PubMed, Latin American and Caribbean Health Sciences Literature Database, the metaRegister of Controlled Trials ( www.controlledtrials.com ), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform ( www.who.int/ictrp/search/en ). We did not impose any date or language restrictions in the electronic search for trials. We last searched the electronic databases on April 27, 2021. The Cochrane systematic review includes our detailed search strategy for each electronic database.
TRIAL SELECTION
Pairs of authors independently reviewed titles and abstracts to identify citations that definitely or possibly were eligible based on our inclusion criteria. The final eligibility decision was based on independent review by 2 authors of the full text of articles; disagreements were resolved by discussion.
OUTCOMES OF INTEREST
The primary review outcomes considered mainly the acute phase of EKC, including decreasing the mean time (measured in days) from initiation of treatment until resolution of signs or symptoms and/or increasing the proportion of patients with resolutions of signs or symptoms by 7 days after treatment. In trials where many signs and symptoms were evaluated individually, conjunctival injection or “redness” was chosen as the primary sign and ocular discomfort or pain as the primary symptom.
Secondary outcomes focused mainly on the chronic, or delayed, phase, including the proportion of participants in whom SEI had developed by day 21 after treatment initiation; the proportion of participants in whose eyes SEI had disappeared by day 21 after treatment initiation; and the proportion of participants who discontinued medication for SEI without rebound signs and symptoms by day 21 after initiation of treatment. Additional outcomes included the proportion of participants with evidence of adenoviral eradication based on results of negative cell culture immunofluorescence assay, polymerase chain reaction, or other methods by day 14 after treatment initiation; the proportion of initially unaffected fellow eyes that developed signs/symptoms of infection within 7 days of onset of signs/symptoms in the first eye; the proportion of participants who experienced adverse events including severe ocular discomfort, redness, or discharge, which might be signs of toxicity; intraocular pressure elevation ≥22 mm Hg; and costs of interventions.
DATA COLLECTION AND ASSESSMENT OF TRIALS FOR RISK OF BIAS
For all outcomes, we recorded the available data for each outcome closest to the time points specified. Within pairs of review authors, authors independently extracted and then cross-verified data from the included studies regarding trial characteristics, methods, participants, interventions, outcomes, and funding sources. We used the web-based software Covidence to store and manage the data. We compared participant and design characteristics among the trials to judge clinical and methodologic heterogeneity in Review Manager. We attempted to contact study investigators by electronic mail when necessary. We also sought complete trial information from pharmaceutical websites wherever possible. We did not impute any outcome data. Review authors also worked in pairs independently to evaluate the included studies for potential sources of bias based on guidelines in the Cochrane Handbook. We judged each study to have been at low, high, or unclear risk (whenever the information provided was insufficient to make an assessment) of bias of each type and documented reasons for these assessments. We resolved discrepancies through discussion.
DATA SYNTHESIS AND ANALYSIS
We ascertained whether the design of each included trial and whether investigators randomized at the participant or eye level. We estimated the difference in means (“mean difference”) for comparison of continuous outcomes. We calculated summary risk ratios (RRs) with 95% confidence intervals (CIs).
We calculated the I 2 statistic (%) to determine the proportion of variation in outcomes due to statistical heterogeneity; we considered a value >50% to suggest substantial heterogeneity. We compared outcomes for topical pharmacologic interventions vs inactive controls (placebo, artificial tears, saline, vehicle, or no treatment), for topical pharmacologic treatments vs active controls, and for steroid-containing treatments vs inactive controls. We performed meta-analysis when clinical and methodological heterogeneity was acceptable. When <3 studies were included in an analysis, we used a fixed-effect model as advised in the Cochrane Handbook. We explored comparisons between treatments and controls and by subgroups to explain observed heterogeneity in effect estimates from individual studies whenever sufficient data (≥2 studies in ≥1 subgroup) were available. When the quality of the available data from a study prevented meaningful analysis, we omitted the study from quantitative analyses and reported the data in a narrative format. All analyses were performed in RevMan Web. We also assessed the certainty of evidence for each review outcome following the GRADE approach. A priori, we judged the design of each included study to confer a high certainty of evidence and downgraded certainty to moderate, low, or very low when there was evidence of high risk of bias, inconsistency, indirectness, or imprecision.
RESULTS
The electronic searches yielded 4981 records, of which we screened 4166 after removing duplicates ( Figure 1 ). We obtained and screened 101 full-text reports that were potentially relevant. We included in this review 10 RCTs, published in 14 reports. Another 4 trials (6 records) were either “ongoing” (in progress) or “awaiting classification” pending receipt of additional information from the trial investigators or sponsors.
DESCRIPTION OF INCLUDED STUDIES
All included studies were single-center studies, conducted in Asia (n = 4), the Middle East (n = 3), Europe (n = 2), and Africa (n = 1). The 10 studies enrolled 892 participants and reported outcomes for 834 (93.5%) participants; a median number of 71 (interquartile range [IQR] 28-82) participants were enrolled per study. All 10 included studies were parallel-group RCTs: in 6 RCTs, 1 eye of each participant was treated; in the other 4, both eyes of some or all participants were assigned to the same intervention ( Table 1 ). We analyzed data from studies that had assessed outcomes in both eyes separately in the absence of information on intraperson correlation. No trial was judged to have low risk of bias across all criteria ( Figure 2 ). We judged 6 of the 10 trials to have had unclear or high-risk of bias in ≥5 of the 6 domains assessed. Reporting bias (selective reporting bias) was the domain for which we judged the largest number of trials to have been deficient.
| Study and Year | Country | Intervention | Control | Participants Randomized/Analyzed (n/n) | Intervention Duration | Note | |
|---|---|---|---|---|---|---|---|
| Intervention Arm | Control Arm | ||||||
| Comparator: Artificial tears or saline | |||||||
| Trauzettel-Klosinski and associates, 1980 | Germany | Dexamethasone 0.1% + neomycin | Polyvinylpyrrolidone AT | 18/35 | 18/18 | Tapered over 6 weeks | |
| Ward and associates, 1993 | The Philippines | Trifluridine 1% | Polyvinyl alcohol AT | 25/25 | 25/25 | 3 weeks | 3-arm trial |
| Tabbara and Jarade, 2001 | Saudi Arabia | Ganciclovir ung 0.15% | Nonpreserved AT | 9/9 | 9/9 | “Until complete resolution” | Conference abstract |
| Kovalyuk and associates, 2017 | Israel | PVP-I 1.0% + dexamethasone 0.1% | Hydroxypropyl methylcellulose AT | 23 participants/17 eyes | 25 participants/ 25 eyes | 7 days | 3-arm trial |
| Elwan, 2020 | Egypt | PVP-I 5% | “Normal saline” | 200/200 | 150/150 | 3 months (or until the patient recovered) | |
| Ricciardelli and associates, 2021 | Italy | PVP-I 0.6% | Hyaluronate AT | NR/34 | NR/25 | 20 days | |
| Comparator: Steroid or steroid plus antimicrobial agent | |||||||
| Ward and associates, 1993 | The Philippines | Trifluridine 1% | Dexamethasone 0.5% | 25/25 | 25/25 | 3 weeks | 3-arm trial |
| Kovalyuk and associates, 2017 | Israel | PVP-I 1.0% + dexamethasone 0.1% | Dexamethasone 0.01% | 23 participants/17 eyes | 26 participants/ 25 eyes | 7 days | 3-arm trial |
| Bhargava and Kumar, 2019 | India | Tacrolimus 0.03% | Dexamethasone 0.05% | 45/45 | 45/45 | 6 months | |
| Rafe and associates, 2020 | Pakistan | CsA 0.05% | Loteprednol 0.5% | 44/44 | 44/44 | Until SEI resolution | |
| Gouider and associates, 2021 | Tunisia | CsA 0.5% | FML 0.1% | 23 participants/33 eyes | 28 participants/37 eyes | 4 months | Study reported eye-level data |
| Matsuura and associates, 2021 | Japan | FML 0.1% + PVA-I | FML 0.1% + levofloxacin 1.5% | 14/14 | 13/13 | 14 days | PVA-I concentration equivalent to PVP-I 0.055% |
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