Mediators of the Effect of Corneal Cross-Linking on Visual Acuity for Fungal Ulcers: A Prespecified Secondary Analysis From the Cross-Linking-Assisted Infection Reduction Trial

Purpose: The purpose of this study was to determine whether astigmatism or corneal scarring is mediating the reduced visual acuity among patients with fungal keratitis randomized to corneal cross-linking (CXL). Design: This was a prespecified exploratory outcome from an outcome-masked, 2 x 2 factorial design, randomized controlled clinical trial. Study Participants: Consecutive patients presented with moderate vision loss from a smear-positive fungal ulcer at Aravind Eye Hospital, Madurai, India. Intervention: Study eyes were randomized to one of 4 treatment combinations using an adaptive randomization protocol. The treatment arms included (1) topical natamycin 5% alone, (2) topical natamycin 5% plus CXL, (3) topical amphotericin B 0.15% alone, and (4) topical amphotericin 0.15% plus CXL. Best spectacle-corrected visual acuity (BSCVA), contact lens over-refraction, and scar size and depth as measured by a masked study ophthalmologist using a standardized protocol were recorded at 3 months. Pentacam Scheimpflug imaging was also obtained at 3 months. Main Outcome Measures: BSCVA and contact lens over-refraction, infiltrate and/or scar size and depth, total astigmatism of the front and back of the cornea, total lower-order and higher-order aberrations of the anterior and posterior cornea, and total densitometry of the anterior, central, and posterior stroma were recorded. We performed a mediation analysis looking at the proportion of the effect of CXL on BSCVA that was mediated through scar size, scar depth, astigmatism and density. Results: BSCVA at 3 months was available for 99 of 111 patients (89%) who had a mean of 0.82-LogMAR (SD 0.68). Three-month infiltrate and/or scar size (P < 0.001), depth (P < 0.001), and densitometry (P = 0.001) were statistically significant predictors of 3-month BSCVA. Astigmatism seemed to mediate 23% of the effect of CXL on BSCVA, whereas scar size mediated 23%, scar depth 17%, and densitometry 7%. Conclusions: Corneal scarring and astigmatism are mediators of worse visual acuity after cross-linking in fungal keratitis. Corneal densitometry may be a helpful cornea-specific variable for clinicians and researchers in determining the effect of corneal scarring on visual acuity in specific patients and as an objective study outcome.

Automated summary

The purpose of this study was to determine whether astigmatism or corneal scarring is mediating the reduced visual acuity among patients with fungal keratitis randomized to corneal cross-linking (CXL). The results showed that astigmatism, scar size, scar depth, and corneal density may affect the effectiveness of corneal cross-linking treatment on visual acuity.