Evaluation of risk factors for treatment failure in canine patients undergoing photoactivated chromophore for keratitis - corneal cross-linking (PACK-CXL): a retrospective study using additive bayesian network analysis

Abstract

Background: Infectious keratitis is a common ophthalmic condition in canine patients. Sequelae can include keratomalacia and corneal perforation, a vision threatening outcome. Photoactivated chromophore for keratitis - corneal cross-linking (PACK-CXL) is a non-surgical, adjunctive treatment method for infectious keratitis. The goal of this retrospective, multicenter study was to determine risk factors for treatment failure following PACK-CXL in canine patients suffering from suspected infectious keratitis. Medical records from four veterinary ophthalmology services were reviewed, and information related to patient demographics, ophthalmic findings, the PACK-CXL protocol used, and epithelialization time was collected and analyzed. Due to the potential for intervariable relationships, an additive Bayesian network (ABN) analysis was performed to evaluate these complex relationships.

Results: Records for 671 eyes (668 dogs) were included in the analysis. Based on the ABN, in the population included here, patients who underwent an accelerated PACK-CXL protocol were less likely to experience treatment failure versus patients treated with a slow protocol. Mutual dependencies between exposure variables were identified by ABN, which would have been overlooked using classical regression. Corneal re-epithelialization time was shortened following PACK-CXL combined with topical medical therapy compared to PACK-CXL alone.

Conclusions: No risk factors associated with treatment failure were identified in the population included in the present study. Canine patients may benefit from the use of accelerated PACK-CXL protocols, especially when combined with topical antibiotics and anti-collagenolytic therapy. The reasons for this apparent positive impact on treatment outcome remain unclear.

Keywords: Additive bayesian network; Canine; Corneal Ulcer; Directed acyclic graph; Infectious keratitis; PACK-CXL; Photoactivated chromophore for keratitis – corneal cross-linking.

Fig. 1

Evaluation of risk factors associated with PACK-CXL treatment failure (primary treatment outcome): Additive Bayesian network (ABN) analysis. The nodes (squares, rectangles and ovals) represent exposure variables, and the red square represents the primary treatment outcome (treatment success/failure). The arcs represent the relationships between variables, with a dashed line indicating a negative association, and a solid line indicating a positive association. Arc thickness represents the strength of support for the association. Oval nodes represent variables with Gaussian distributions. Quadratic nodes represent variables with binomial distributions. For the variables without baseline indicated in the graph, the baseline value was “no”. Acceleration is the only exposure variable directly associated with the outcome. No other variables were directly linked to the outcome, but some variables were indirectly linked to the outcome through acceleration

Fig. 2

Corneal re-epithelialization time (secondary treatment outcome) of PACK-CXL + topical medical therapy compared to PACK-CXL alone: Kaplan-Meier survival analysis. The median survival time (dashed line) for each group represents the length of time within which the cornea of 50% of patients had re-epithelialized, which was 21 days (95% CI from 16 to 23 days), and 14 days (95% CI from 14 to 15 days), for the groups receiving CXL only, and CXL/medical treatment, respectively (p < 0.001). The straight lines represent the Kaplan-Meier curves and the surrounding dilute colored zones the 95% CIs. Tx: Treatment

Fig. 3

Forest Plot for Cox proportional hazards model. Hazard ratio (HR) marked as black square, 95% CI as horizontal line. A HR < 1 indicates a reduced “risk” of epithelialization compared to the reference group. A HR > 1 indicates a higher “risk” of epithelialization compared to the reference group. Tx: Treatment. Dx: Disease. Variables for the model were selected based on a standard step-wise selection process; details can be found in Supplementary file 2. Based on this approach, age, skull type, time until referral, AB prior, steroids prior, systemic disease, nasolacrimal disease, ulcer depth, keratomalacia, riboflavin carrier, riboflavin concentration, and fluence were not included in the Cox proportional hazard regression