Hafezi et al.

Eye and Vision (2023) 10:36 Eye and Vision

https://doi.org/10.1186/s40662-023-00354-1

SHORT REPORT Open Access

Rates of infectious keratitis and other ocular

surface adverse events in corneal cross‑linking
for keratoconus and corneal ectasias performed
in an office‑based setting: a retrospective
cohort study
Farhad Hafezi1,2,3,4,5* , Emilio A. Torres‑Netto2, Leonard Kollros2, Nan‑Ji Lu2, Nikki Hafezi2, Cosimo Mazzotta6,7,8,
M. Enes Aydemir1,2 and Mark Hillen2

Abstract
Background This study aimed to compare the complication rates of epithelium-off corneal cross-linking (epi-off
CXL) performed in an office-based setting with those of epi-off CXL performed in an operating room.
Methods A retrospective cohort study, comprising 501 consecutive epi-off CXL procedures, performed in a non-ster‑
ile procedure room without laminar flow ventilation at the ELZA Institute in Zurich, Switzerland, between November
2015 and October 2021, was conducted.
Results No cases of postoperative infectious keratitis were observed, while sterile infiltrates occurred in 10 out of 501
(2.00%) patients, all of whom responded well to topical steroid therapy. Delayed epithelialization (> 7 days) occurred
in 14 out of 501 (2.79%) patients. No other adverse events were noted.
Conclusions Office-based epi-off CXL does not appear to be associated with an increased risk of complications
when compared to operating room settings.
Keywords Corneal cross-linking, Office-based, Keratoconus, Cornea, Slit lamp, Epithelium-off, Infectious keratitis,
Sterile infiltrates

Background
*Correspondence: Corneal cross-linking (CXL) is a surgical procedure com-
Farhad Hafezi
[email protected] monly performed to halt the progression of corneal ecta-
1
Laboratory for Ocular Cell Biology, Center for Applied Biotechnology sias like keratoconus or postoperative ectasia [1]. CXL
and Molecular Medicine, University of Zurich, Zurich, Switzerland requires the corneal stroma to be saturated with ribo-
2
ELZA Institute, Dietikon, Switzerland
3
USC Roski Eye Institute, University of Southern California, Los Angeles, flavin, which is then irradiated with ultraviolet (UV)-A
CA, USA light. This reaction results in the photochemical activa-
4
Faculty of Medicine, University of Geneva, Geneva, Switzerland tion of riboflavin and the generation of reactive oxy-
5
Dept. of Ophthalmology, University of Wenzhou, Wenzhou, China
6
Departmental Ophthalmology Unit, Alta Val d’Elsa Hospital, AUSL gen species (ROS), which covalently cross-link stromal
Tuscany South-East, Siena, Italy molecules (predominantly collagen, but also proteogly-
7
Postgraduate Ophthalmology School, University of Siena, Siena, Italy cans), which renders a stiffer, biomechanically stronger
8
Siena Crosslinking Center, Monteriggioni, Siena, Italy
cornea more resistant to ectasia progression. The CXL

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Hafezi et al. Eye and Vision (2023) 10:36 Page 2 of 6

procedure typically involves epithelial cell debridement registered with the local ethics committee, the Zurich
of the central 7–9 mm of the cornea (known as “epi-off ” Kantonale Ethikkommission (ZKE), under the reference
CXL), since riboflavin is a large molecule (376.36 g/mol) REG-2021-01121. As the study was anonymized and
and does not pass through the epithelium easily [1, 2]. retrospectively examined outcomes data only, the ethics
Once UV irradiation is complete, epithelial cells repop- committee waived the need for written informed consent
ulate the corneal surface over the next few days; during and ethical approval for the study. To clarify, all patients
this period, patients require topical antimicrobial and had submitted written informed consent to undergo the
pain management. original surgical procedure.
Despite the associated costs and administrative burden,
CXL is typically performed in an operating room, as the
sterile environment is considered to be a safe setting for CXL procedure
performing epithelial debridement, riboflavin instilla- All patients in this study underwent epi-off CXL. Ten
tion, and the irradiation of a cornea with a large epithelial minutes prior to the procedure, patients received topical
defect for a period of up to 30 min [3]. However, the ROS ocular anesthesia drops: oxybuprocaine (oxybuprocaine
generated by the UV-riboflavin photochemical reaction hydrochloride, 4 mg/mL, Théa Pharma SA, Clermont-
also reduce the microbial load on the cornea to such an Ferrand, France) followed by one drop of Tetracain (tet-
extent that riboflavin/UV CXL can be used to treat cases racaine 1%, Théa Pharma SA, Clermont-Ferrand, France)
of bacterial, fungal, or mixed bacterial/fungal infections every 3 min for a 9-min period. After being brought into
of the cornea [4] in a procedure called photoactivated the procedure room and the surgical area covered with
chromophore for keratitis-CXL (PACK-CXL) [5]. PACK- sterile drapes, the periorbital region was thoroughly dis-
CXL has been successfully used as an infectious keratitis infected with sterile cotton wool buds soaked in octeni-
monotherapy, as well as in combination with antimicro- dine hydrochloride (Octenisept; Schülke & Mayr GmbH,
bial pharmacotherapy [5–7]. Considering the cost and Norderstedt, Germany). An eyelid speculum was placed,
administrative burdens of utilizing an operating room [3, and sterile surgical gauze was secured with surgical tape
8], its main advantage, sterility, appears to be negated by laterally to the temporal canthus to absorb riboflavin
the antimicrobial effect of CXL/PACK-CXL. The fact that solution run-off. All persons involved wore masks and
comprehensive antimicrobial prophylaxis is applied after sterile gloves, and all surfaces encountering the patient
UV irradiation is complete raises the possibility that CXL were sterile.
could be performed in a non-sterile procedure room Epithelial debridement was performed mechanically
without an additional infection risk compared to CXL either with a hockey blade, an Amoils brush, or with
performed in an operating room [3, 6]. This mirrors the 40% ethanol applied with a sterile cotton swab in a cir-
transition of intravitreal anti-vascular endothelial growth cular tapping manner for around 30–35 s, replaced with
factor (VEGF) therapies [9–12] and even cataract surgery a freshly soaked swab and tapped for a further 30–35 s
[13], from the operating theater to doctors’ offices or pro- to loosen the epithelium, then wiped away in a circular
cedure rooms. motion, then rinsed with balanced salt solution (Table 1).
The focus of this paper is narrow: it does not report This step was performed either with the patient lying
on the clinical results of CXL for keratoconus, but solely supine in a reclining chair (n = 488) or seated upright at
retrospectively examines the adverse event rates of CXL a slit lamp (n = 13). Riboflavin instillation was performed
performed in a procedure room over a five-year period every 2 min for 10 min on all patients lying supine in a
in a single office-based non-sterile setting in order to reclining chair. Over this nearly seven-year period, only
compare these rates with published adverse event rates of two riboflavin solutions were used (Table 1): Ricro-
CXL performed in an operating room setting. lin + (Sooft, Montegiorgio, Italy) was used on the first 331
eyes, then Ribo-Ker (EMAGine AG, Zug, Switzerland;
Methods n = 170). Both solutions share hypo-osmolarity and the
Surgical technique absence of carriers like dextran or hydroxypropyl methyl-
Patients cellulose (HPMC). The riboflavin used was changed
This retrospective cohort study involved the analysis of because of availability issues during the COVID-19 pan-
individuals who underwent epi-off CXL procedures for demic. The UV irradiation protocol used (in terms of irra-
the treatment of corneal ectasia in an office-based, non- diation duration and intensity) was dependent on the age
sterile setting (a 16 ­m2 procedure room without laminar of the patient, severity of the ectasia, corneal thickness,
flow ventilation or humidity control) at the ELZA Insti- and the establishment of newer cross-linking protocols.
tute in Zurich, Switzerland, between November 2015 and Irradiation was performed by the cross-linking devices
October 2021, as previously described [3]. The study was described in Table 1, and the duration of irradiation
Hafezi et al. Eye and Vision (2023) 10:36 Page 3 of 6

Table 1 Baseline demographics and cross-linking procedure ranged from 5 to 30 min, intensity ranged from 3 to 18
parameters used mW/cm2 and fluence ranged from 5.4 to 10 J/cm2.
Parameter Value Corneal pachymetry was measured using the SP-1000
(Tomey, Nagoya, Japan) at the thinnest points imme-
Gender diately after riboflavin application and at the end of UV
Female 152 irradiation. After the procedure, the eye was thoroughly
Male 349 irrigated with balanced salt solution (BSS), and topical
Age (years) antibiotics Tobradex (0.1% tobramycin–0.3% dexametha-
Mean (SD) 30.7 (12.4) sone, Novartis Pharma, Basel, Switzerland) and Vigamox
Minimum, maximum 5.1, 71.7 (moxifloxacin 0.5%; Alcon, Geneva, Switzerland) were
Operated eye (OD, OS) 255, 246 administered immediately afterward, and a bandage con-
Preoperative pachymetry (µm) tact lens (Air Optix Night&Day; Ciba Vision AG) was
Mean (SD) 460.9 (60.3) used to cover the eye. Finally, the speculum was removed.
Minimum, maximum 152, 596 The post-procedural antimicrobial and pain prophylaxis
Ectasia type (patients, n) regimen was as previously described [14].
Keratoconus 440
Post-LASIK ectasia 28 Analysis of postoperative infections
Pellucid marginal degeneration 25 After the procedure, we assessed the following param-
Post-radial keratotomy 4 eters: signs of postoperative microbial infection (within
Terrien marginal degeneration 3 the first 14 days), sterile infiltrates (within the first
Post-PRK ectasia 1 14 days), and delayed epithelialization (> 7 days), which
Epithelium removal method (eyes, n) were observed via slit lamp biomicroscopy.
Amoils brush 18
Ethanol/cotton swab 150
Results
Hockey knife 333 A total of 501 patients with corneal ectasia received CXL
Epithelial removal location (eyes, n) in an office-based, non-sterile setting between Novem-
Reclining chair (supine) 488 ber 2014 and October 2021, with the majority (440/501,
Slit lamp (sat upright) 13 87.82%) having keratoconus as the indication for the pro-
Riboflavin applied (eyes, n) cedure. The other indications were post-LASIK ectasia
Ricrolin + 298 (28/501, 5.59%), pellucid marginal degeneration (25/501,
Ribo-Ker 203 4.99%), radial keratotomy (4/501, 0.80%), Terrien mar-
Riboflavin saturation duration (eyes, n) ginal degeneration (3/501, 0.60%), and post-PRK ecta-
10 min 72 sia (1/501, 0.20%). No cases of infectious keratitis were
20 min 429 observed. Peripheral sterile infiltrates occurred in ten
UV irradiation duration (mm:ss) cases (10/501, 2.00%), all of which reacted well to topi-
Mean (SD) 14:56 (07:25) cal steroids. Delayed epithelialization of more than seven
Minimum, maximum 4:38, 30:00 days occurred in 14/501 (2.79%) patients, with all corneas
Mode 10:00 showing full epithelialization after 12 days (Additional
UV irradiation intensity (eyes, n) file 1: Table S1).
3 mW/cm2 173
9 mW/cm2 319 Discussion
2
18 mW/cm 9 In this study of epi-off CXL performed in an office-
UV irradiation location (eyes, n) based, non-sterile procedure room setting, adverse
Operating theater-microscope 453 events were rare, with observed rates ranging from 0%
Slit lamp 48 to 2.79%. These rates are comparable to epi-off CXL
UV irradiation device (eyes, n) complication rates reported in the literature. For exam-
C-Eye 88 ple, in 2009, Koller et al. described a case series of 117
CXL-365 Vario 413 eyes with corneal ectasia that underwent Dresden pro-
SD = standard deviation; LASIK = laser in situ keratomileusis; PRK = tocol CXL (30 min of 3 mW/cm2 UV irradiation at 3
photorefractive keratectomy; UV = ultraviolet; CXL = corneal collagen cross-
linking
mW/cm2 intensity) [15]. Sterile infiltrates occurred in
Hafezi et al. Eye and Vision (2023) 10:36 Page 4 of 6

9/117 (7.69%) of eyes and stromal scarring in three eyes basal stroma. This measure aims to protect the corneal
(2.56%); no cases of infectious keratitis were observed. endothelium from damage, as established by the Dresden
There have been several individual case reports describ- protocol.
ing infectious keratitis following epi-off CXL [16–20], Most patients received 9 mW/cm2 UV intensity for
but there are few data on larger patient groups, with the 10 min. However, for certain groups of patients (predom-
exception of Shetty et al. [21], who observed four cases inantly pediatric) with particularly aggressive disease,
of infectious keratitis amongst 2350 patients (0.17%). the classic Dresden protocol (3 mW/cm2 for 30 min) [26]
Serraro et al. reviewed the adverse event rates of epi- was applied for maximal corneal strengthening effect.
on and epi-off CXL procedures of 27 publications that The study being performed by a single surgeon, has the
comprised a total of 9397 eyes, 9006 of which were benefit of consistency and removing any variables that
epi-off procedures [22]. In terms of epi-off procedures, may be introduced by multiple surgeons, but may also
infectious, bacteria, viral and herpetic keratitis rates limit the generalizability of the results. Finally, some pro-
were 2.26% (45/1990), 0.12% (2/1659), 0.62% (1/161) cedures were performed with the patient sitting upright
and 0.18% (4/2182), respectively. Corneal infiltrate at the slit lamp to receive the UV irradiation, whereas
rates were 2.0% (55/2776), and scarring occurred in other patients were irradiated lying supine. However, it
1.59% (49/3089). Reports by Dhawan et al. and Koppen has been shown that the position in which the patient
et al. described four cases of infectious keratitis in 117 receives UV irradiation does not materially influence the
eyes (3.42%) undergoing epi-off Dresden protocol [23, riboflavin distribution or depth of cross-linking effect [3,
24]. 27, 28].
While it is recognized that environmental heat and It is worth comparing the adverse event rates of CXL
humidity can contribute to pathogen growth, and par- with other ophthalmological procedures that were pre-
tially explain regional differences in rates and types of viously always performed in an operating room setting
infectious keratitis, it is also reasonable to presume that and are now increasingly being performed as office-based
these environmental factors could also influence post- procedures. These include intravitreal injections (IVIs)
procedural infection rates. However, given the strong of anti-VEGF drugs for the treatment of neovascular dis-
pathogen-killing effects of CXL, rendering the cornea eases of the retina [9–12] or cataract surgery [13], with
effectively “sterile” [5–7], the main drivers of post-proce- the intention of making cost and resource savings [9–13].
dural infection risk are not the method, setting, or envi- Undoubtedly, injecting a substance into the vitreous cav-
ronmental conditions that exist during the procedure. ity or performing intraocular surgery has the potential for
Rather, the drivers are in how carefully the cornea is han- serious infectious consequences. Nevertheless, published
dled after CXL is complete, highlighting the importance data show that IVI or cataract surgery performed in an
of patients carefully adhering to their post-procedural office-based or examination room setting does not result
topical antimicrobial drug regimen and not rubbing their in increased endophthalmitis rates [9–13]. For example,
eyes [14]. one meta-analysis of 1,275,815 IVIs found no differ-
This study has certain limitations. It is retrospective in ence in endophthalmitis rates between those performed
nature and compares adverse event rates with those pub- in an office or an operating room setting [9]. Ianchulev
lished in the literature, rather than having an operating et al. reported the results of a large single-center retro-
room control group. During the period under considera- spective study of office-based cataract surgery (13,507
tion, the UV irradiation device and the riboflavin solu- patients; 21,501 eyes), finding that “office-based efficacy
tion were changed. Even though the beam profiles were outcomes were consistently excellent, with a safety pro-
similar and UV output intensities were matched, the file expected of minimally invasive cataract procedures
riboflavin solutions were similar in composition, both performed in ambulatory surgical centers and hospital
being hypo-osmolar, HPMC, and dextran-free. Moreover, outpatient departments” [13]. The safety of intraocular
different UV irradiation intensities and durations were procedures and surgeries conducted in an office-based
applied, reflecting the evolution of clinical practice in setting has been shown to be comparable to that of pro-
CXL in Europe during this period. cedures performed in an operating room. In addition,
The study included both thin (330 to < 400 µm) and the UV-riboflavin photochemical reaction inherent in
ultra-thin (200 to < 330 µm) corneas treated with the CXL procedures is known to produce sufficient ROS to
sub400 protocol [25]. This protocol adapts the UV flu- reduce the microbial load significantly [4]. This reduc-
ence delivered to patients’ individual thinnest-point tion in microbial load is so substantial that CXL can be
pachymetries to cross-link the cornea while maintaining successfully employed as a treatment for infectious kera-
an approximately 70 µm uncross-linked safety margin of titis [6], even as a stand-alone procedure [6, 29]. Given
Hafezi et al. Eye and Vision (2023) 10:36 Page 5 of 6

these established facts, the findings from our study lend Supplementary Information
further support to the concept of performing epi-off The online version contains supplementary material available at https://​doi.​
CXL safely in a procedure room. For the purposes of this org/​10.​1186/​s40662-​023-​00354-1.
discussion, a procedure room is defined as a room spe-
Additional file 1: Table S1. Adverse events narrative.
cifically designed and equipped for performing medical
procedures. It is characterized by a ventilation system
that ensures adequate airflow and minimizes the risk of Acknowledgements
Not applicable.
infection, and thus makes it an acceptable alternative to
an operating room. Author contributions
Transitioning CXL from operating rooms to proce- FH, ET, LK, and NL had full access to all the data in the study and take respon‑
sibility for the integrity of the data and the accuracy of the data analysis.
dural rooms should significantly reduce costs, enhancing Conception and design: FH, ET, LK. Data collection: all authors. Analysis and
accessibility in low-to-middle income countries (LMICs) interpretation: all authors. Drafting the manuscript: FH, MH, ET. Critical revi‑
where financial barriers limit care. This shift has broad sion of the manuscript: all authors. Supervision: FH. All authors reviewed and
approved the final version of the manuscript.
economic implications. Given the prevalence of vision
loss due to corneal ectasias, early CXL intervention is Funding
crucial for vision preservation and prolonged economic No funding was received for the study.

productivity. This cost reduction and increased access Availability of data and materials
could yield wider societal economic benefits, particularly Data are available from the corresponding author upon reasonable request.
in LMICs that have higher levels of currently unmet clini-
cal need for CXL to treat corneal ectasias. Declarations
Ethics approval and consent to participate
All procedures were performed in accordance with relevant guidelines. The
Conclusion ethics committee of Canton Zurich (Zurich Kantonale Ethikkommission,
BASEC-Nr. Req-2021-01121) waived the need for written informed consent
The findings from this retrospective analysis of 501 epi-
and ethical approval for the study.
off CXL procedures indicate that there is no increase in
the risk of postoperative infectious keratitis when per- Consent for publication
Not applicable.
forming epi-off CXL in a procedure room compared with
operating room-based procedures previously published Competing interests
in the literature. This suggests that surgeons can be con- NH is CEO of EMAGine AG, a company producing a CXL device. FH holds a
patent on a UV light source (PCT/CH 2012/000090) and is CSO of EMAGine
fident that epi-off CXL can be safely performed outside
AG. FH is an editorial board member of Eye and Vision. The other authors have
of the operating room setting. The fact that every CXL no proprietary or commercial interest in any of the materials discussed in this
procedure reduces the microbial load on the cornea due article.
to the UV-riboflavin photochemical reaction [5–7], and
has been shown to be effective enough to be used as a Received: 6 March 2023 Accepted: 16 July 2023
monotherapy for the treatment of bacterial and fungal Published: 1 September 2023
infectious keratitis, is also reassuring.
Furthermore, as transepithelial procedures have
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lamp: no clinically relevant changes in corneal riboflavin distribution dur‑
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