In this study of epi-off CXL performed in an office-based, non-sterile procedure room setting, adverse events were rare, with observed rates ranging from 0% to 2.79%. These rates are comparable to epi-off CXL complication rates reported in the literature. For example, in 2009, Koller et al. described a case series of 117 eyes with corneal ectasia that underwent Dresden protocol CXL (30 min of 3 mW/cm2 UV irradiation at 3 mW/cm2 intensity) [15]. Sterile infiltrates occurred in 9/117 (7.69%) of eyes and stromal scarring in three eyes (2.56%); no cases of infectious keratitis were observed. There have been several individual case reports describing infectious keratitis following epi-off CXL [16,17,18,19,20], but there are few data on larger patient groups, with the exception of Shetty et al. [21], who observed four cases of infectious keratitis amongst 2350 patients (0.17%). Serraro et al. reviewed the adverse event rates of epi-on and epi-off CXL procedures of 27 publications that comprised a total of 9397 eyes, 9006 of which were epi-off procedures [22]. In terms of epi-off procedures, infectious, bacteria, viral and herpetic keratitis rates were 2.26% (45/1990), 0.12% (2/1659), 0.62% (1/161) and 0.18% (4/2182), respectively. Corneal infiltrate rates were 2.0% (55/2776), and scarring occurred in 1.59% (49/3089). Reports by Dhawan et al. and Koppen et al. described four cases of infectious keratitis in 117 eyes (3.42%) undergoing epi-off Dresden protocol [23, 24].

While it is recognized that environmental heat and humidity can contribute to pathogen growth, and partially explain regional differences in rates and types of infectious keratitis, it is also reasonable to presume that these environmental factors could also influence post-procedural infection rates. However, given the strong pathogen-killing effects of CXL, rendering the cornea effectively “sterile” [5,6,7], the main drivers of post-procedural infection risk are not the method, setting, or environmental conditions that exist during the procedure. Rather, the drivers are in how carefully the cornea is handled after CXL is complete, highlighting the importance of patients carefully adhering to their post-procedural topical antimicrobial drug regimen and not rubbing their eyes [14].

This study has certain limitations. It is retrospective in nature and compares adverse event rates with those published in the literature, rather than having an operating room control group. During the period under consideration, the UV irradiation device and the riboflavin solution were changed. Even though the beam profiles were similar and UV output intensities were matched, the riboflavin solutions were similar in composition, both being hypo-osmolar, HPMC, and dextran-free. Moreover, different UV irradiation intensities and durations were applied, reflecting the evolution of clinical practice in CXL in Europe during this period.

The study included both thin (330 to < 400 µm) and ultra-thin (200 to < 330 µm) corneas treated with the sub400 protocol [25]. This protocol adapts the UV fluence delivered to patients' individual thinnest-point pachymetries to cross-link the cornea while maintaining an approximately 70 µm uncross-linked safety margin of basal stroma. This measure aims to protect the corneal endothelium from damage, as established by the Dresden protocol.

Most patients received 9 mW/cm2 UV intensity for 10 min. However, for certain groups of patients (predominantly pediatric) with particularly aggressive disease, the classic Dresden protocol (3 mW/cm2 for 30 min) [26] was applied for maximal corneal strengthening effect. The study being performed by a single surgeon, has the benefit of consistency and removing any variables that may be introduced by multiple surgeons, but may also limit the generalizability of the results. Finally, some procedures were performed with the patient sitting upright at the slit lamp to receive the UV irradiation, whereas other patients were irradiated lying supine. However, it has been shown that the position in which the patient receives UV irradiation does not materially influence the riboflavin distribution or depth of cross-linking effect [3, 27, 28].

It is worth comparing the adverse event rates of CXL with other ophthalmological procedures that were previously always performed in an operating room setting and are now increasingly being performed as office-based procedures. These include intravitreal injections (IVIs) of anti-VEGF drugs for the treatment of neovascular diseases of the retina [9,10,11,12] or cataract surgery [13], with the intention of making cost and resource savings [9,10,11,12,13]. Undoubtedly, injecting a substance into the vitreous cavity or performing intraocular surgery has the potential for serious infectious consequences. Nevertheless, published data show that IVI or cataract surgery performed in an office-based or examination room setting does not result in increased endophthalmitis rates [9,10,11,12,13]. For example, one meta-analysis of 1,275,815 IVIs found no difference in endophthalmitis rates between those performed in an office or an operating room setting [9]. Ianchulev et al. reported the results of a large single-center retrospective study of office-based cataract surgery (13,507 patients; 21,501 eyes), finding that “office-based efficacy outcomes were consistently excellent, with a safety profile expected of minimally invasive cataract procedures performed in ambulatory surgical centers and hospital outpatient departments” [13]. The safety of intraocular procedures and surgeries conducted in an office-based setting has been shown to be comparable to that of procedures performed in an operating room. In addition, the UV-riboflavin photochemical reaction inherent in CXL procedures is known to produce sufficient ROS to reduce the microbial load significantly [4]. This reduction in microbial load is so substantial that CXL can be successfully employed as a treatment for infectious keratitis [6], even as a stand-alone procedure [6, 29]. Given these established facts, the findings from our study lend further support to the concept of performing epi-off CXL safely in a procedure room. For the purposes of this discussion, a procedure room is defined as a room specifically designed and equipped for performing medical procedures. It is characterized by a ventilation system that ensures adequate airflow and minimizes the risk of infection, and thus makes it an acceptable alternative to an operating room.

Transitioning CXL from operating rooms to procedural rooms should significantly reduce costs, enhancing accessibility in low-to-middle income countries (LMICs) where financial barriers limit care. This shift has broad economic implications. Given the prevalence of vision loss due to corneal ectasias, early CXL intervention is crucial for vision preservation and prolonged economic productivity. This cost reduction and increased access could yield wider societal economic benefits, particularly in LMICs that have higher levels of currently unmet clinical need for CXL to treat corneal ectasias.