Table 1.

Summary of all prospective or randomized clinical trials for cross-linking in IK over the last 10 years

Author year	Methods	Participants Setting	Groups Intervention	Outcomes	Time Fu
Price 2012	Pilot study Prospective Non - randomized	40 patients USA	Organisms Bacterial 24 eyes (Staph spp, Moraxella, Pseudomonas, Serratia, Enterococcus) Fungal 7 eyes (Penicillium, Fusarium, Aspergillus), Acanthamoeba 2 eyes, Herpes 1 eye. All had Riboflavin CXL treatment ( 4 patients 30 minutes) 36 patients randomized to different UVA light treatment time from 15 to 45 minutes) + standard medical care treatment Infiltrate diameter range: 1 to 12 mm2	The success rate was higher for bacterial infections than fungal infections The two cases of Acanthamoeba did not appear to be significantly influenced
Makdoumi 2012	Pilot study Non-randomized	16 patients Sweden	Organisms Bacterial (Staph spp, Corynebacterium, Micrococcus, Propionibacterium) All received Riboflavin CXL Dresden protocol alone Only 2 patients received additional antibiotic. Corneal ulcer size 0.1 to 2.5 mm	All eyes responded to the photochemical treatment with improvement in symptoms and signs of reduced inflammation. Epithelial healing was achieved in all cases. Antibiotic administration was necessary in two cases
Said 2014	Randomized Clinical trial	21 eyes Egypt	Organisms Bacterial, Fungi or Acanthamoeba Group 1 PACK-CXL Dresden protocol + Standard medical treatment Group 2 Standard medical treatment Infiltrate diameter range in both groups : 2 to 10 mm	Three patients in the control group had corneal perforation, whereas patients treated with PACK-CXL did not experience this complication.	-
Uddaraju 2015	Randomized controlled trial	13 eyes India	Organisms Aspergillus, Fusarium, Unidentified fungal corneal ulcers. Group 1 Standard medical treatment Group 2 Standard medical treatment + Riboflavin CXL Dresden protocol Infiltrate diameter range in both groups : 5 to 7.48 mm	CXL used as adjuvant therapy for recalcitrant deep stromal fungal keratitis did not improve outcomes. The trial was stopped before full enrollment because of a marked difference in the rate of perforation between the 2 groups.	6 weeks
Bamdad 2015	Randomized clinical trial	22 patients Iran	Organisms Bacterial not species not specified Group 1 Standard medical treatment Group 2 Standard medical treatment + Riboflavin CXL Dresden protocol Infiltrate diameter 19.25 mm2	Beneficial effect of CXL in patients with moderate bacterial keratitis. In addition to accelerating epithelialization, this method shortens the course of treatment and may minimize or remove the need for surgery or other serious sequelae, such as corneal perforation.	-
Venkatesh Prajna 2020	Randomized clinical trial	403 patients India	Organisms: Filaments Group 1: natamycin alone, Group 2: natamycin plus CXL, Group 3: amphotericin alone, and Group 4: amphotericin plus CXL. Riboflavin CXL Dresden protocol Moderate size corneal ulcers	Unable to find a difference in 24-hour culture positivity between those randomized to amphotericin and those randomized to natamycin when evaluated as a group regardless of whether or not they received CXL (coefficient 1.10; 95% CI, 0.47e2.54; P 1/4 0.84). No difference in infiltrate or scar size, percentage of epithelialized or adverse events when comparing CXL with no CXL or the 2 topical medications.	3 months

PACK-CXL: Photo Activated Chromophore for Keratitis-Corneal Cross-linking; Spp: species; CXL: cross-linking; BCVA: Best-corrected visual acuity