Tabibian et al.

Eye and Vision (2016) 3:11

DOI 10.1186/s40662-016-0042-x

REVIEW Open Access

PACK-CXL: Corneal cross-linking in

infectious keratitis
David Tabibian1,5*, Cosimo Mazzotta2 and Farhad Hafezi1,3,4

Abstract
Background: Corneal cross-linking (CXL) using ultraviolet light-A (UV-A) and riboflavin is a technique developed in
the 1990’s to treat corneal ectatic disorders such as keratoconus. It soon became the new gold standard in multiple
countries around the world to halt the progression of this disorder, with good long-term outcomes in keratometry
reading and visual acuity. The original Dresden treatment protocol was also later on used to stabilize iatrogenic
corneal ectasia appearing after laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK).
CXL efficiently strengthened the cornea but was also shown to kill most of the keratocytes within the corneal
stroma, later on repopulated by those cells.
Review: Ultraviolet-light has long been known for its microbicidal effect, and thus CXL postulated to be able to
sterilize the cornea from infectious pathogens. This cytotoxic effect led to the first clinical trials using CXL to treat
advanced infectious melting corneal keratitis. Patients treated with this technique showed, in the majority of cases,
a stabilization of the melting process and were able to avoid emergent à chaud keratoplasty. Following those
primary favorable results, CXL was used to treat beginning bacterial keratitis as a first-line treatment without any
adjunctive antibiotics with positive results for most patients. In order to distinguish the use of CXL for infectious
keratitis treatment from its use for corneal ectatic disorders, a new term was proposed at the 9th CXL congress in
Dublin to rename its use in infections as photoactivated chromophore for infectious keratitis -corneal collagen
cross-linking (PACK-CXL).
Conclusion: PACK-CXL is now more frequently used to treat infections from various infectious origins. The original
Dresden protocol is still used for this purpose. Careful modifications of this protocol could improve the efficiency of
this technique in specific clinical situations regarding certain types of pathogens.
Keywords: Infectious Keratitis, Corneal cross-linking, Keratoconus, CXL, PACK-CXL, Corneal ulcer, Ultraviolet light A,
Riboflavin

Background treatment [1, 2]. Easy to perform and efficient after one
The management of corneal ectatic disorder was com- treatment, this technique became the benchmark for the
pletely transformed this past decade through the devel- treatment of progressive keratoconus. With this initial
opment and rise of the corneal cross-linking (CXL) success, the technique was later adapted to treat iatro-
technique in many academic and non-academic clinical genic corneal ectatic disorders [3, 4], bullous keratopathy
settings around the world. Originally developed in Eur- [5, 6], and melting corneal ulcerations [7]. Initially, only
ope, more precisely in Germany and Switzerland, CXL advanced cases of corneal keratitis were treated, but
proposed a new therapeutic alternative to patients with more recently, beginning infections are also responding
progressive keratoconus with the option of stabilizing positively to CXL (Fig. 1, a-d). The number of publica-
the disease through a one-time extra-ocular surgical tions reporting successful treatment of infectious kera-
titis with CXL is increasing. CXL could become a new
* Correspondence: david.tabibian@ngh.nhs.uk alternative to standard treatment of infectious keratitis
1
Laboratory for Ocular Cell Biology, University of Geneva, Geneva, Switzerland in the future.
5
Department of Ophthalmology, Northampton General Hospital,
Northampton, United Kingdom
Full list of author information is available at the end of the article

© 2016 Tabibian et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Tabibian et al. Eye and Vision (2016) 3:11 Page 2 of 5

Fig. 1 Pre- and post-treatment peripheral infectious keratitis. a Anterior segment photography of a patient with early peripheral infectious keratitis
(arrow). b Anterior segment OCT of the lesion. c Anterior segment photography of the same patient 7 days after PACK-CXL (9 mW/cm2 irradiance for
10 min) with resolution of the peripheral infectious keratitis (arrow). d Anterior segment OCT of the lesion at day 7 after PACK-CXL

Review hypo-osmolaric riboflavin solution [12, 13]. This surgery

CXL for corneal ectasia has now been proven to be efficient in the long term
CXL was initially developed to treat progressing corneal with excellent results of disease stabilization over
ectatic disorders such as keratoconus. The idea is to arti- 10 years, and reduces the need of corneal transplant in
ficially strengthen the cornea biomechanically in order this population [13–17]. Further, it not only stops the
to stop the progression of the disease through the com- progression of the disease in adults and in children [18–
bination of ultraviolet light and a photo-reactant within 20], but also flattens the keratometry readings in some
the corneal stroma. The method was initially developed [1, 16]. Under certain circumstances, however, even CXL
by Theo Seiler, Eberhard Spoerl, and Gregor Wollensak. fails to stabilize the biomechanically weakened cornea,
Their first report tested this hypothesis ex vivo on i.e. in pregnancy [21].
porcine corneas and obtained good results, later con- This first accomplishment of halting the progression
firmed in vivo in rabbits and ex vivo on human cor- of keratoconus using CXL led to another application of
neas [2, 8–10]. The first clinical trial was published in this technology. CXL was used to treat iatrogenic cor-
2003 treating 23 eyes with CXL, stabilizing the dis- neal ectatic disorders developed after laser-assisted in
ease in all patients [1]. situ keratomileusis (LASIK) and photorefractive keratec-
CXL was performed using the combination of ultravio- tomy (PRK) [3, 4]. In clinical trials, CXL stabilized Kmax
let light type A (UV-A) and vitamin B2 (also known as values, improved corrected distance visual acuity (CDVA),
riboflavin). The original Dresden protocol mentions that and proved to be an efficient treatment for those rare
the epithelium is mechanically removed, followed by ap- postoperative complications [3, 4, 22–24].
plication of a 0.1 % riboflavin solution [11]. Once the
corneal stroma is soaked with riboflavin, UV-A light A new field to explore
(365 nm) is used to irradiate the cornea for 30 min Very early in the history of CXL, another field was ex-
(3 mW/cm2 irradiance). Riboflavin is a photo-reacting plored where the concept of CXL could also be applied. In
molecule, which produces free radicals within the cor- 2000, Seiler and his team reported the use of CXL for ad-
neal stroma when photoactivated. These free radicals vanced non-infectious corneal melting [25]. This pilot trial
interact with the local collagen and proteoglycan mole- treated four patients with corneal melting of various non-
cules to create new covalent bonds and thus strengthen infectious origins [25]. The rationale was that an increase
the overall biomechanical resistance of the cornea. La- in covalent bonds amongst the collagen molecules might
boratory testing on human corneas reported an increase help stabilize the disease and avoid any à chaud corneal
in corneal rigidity by an average of 300 % after this surgery in these patients. Of four patients, three showed
protocol [2]. Some caution was taken when performing stabilization of the melting process after CXL, whereas the
this surgery as only cornea thicker than 400 μm without last patient continued to progress despite treatment. From
the epithelium were treated in order to avoid damage to this pilot data, it was concluded that CXL could, in some
the endothelium [11]. Specific protocols have since been cases, stabilize the cornea even though a pathological
developed to address the issue of thin corneas using a process had already modified its structure.
Tabibian et al. Eye and Vision (2016) 3:11 Page 3 of 5

PACK-CXL for keratitis additional intervention after PACK-CXL. Healing rate

The treatment of advance corneal melting came back might be different when using PACK-CXL alone and
into clinical perspective 8 years later with a clinical trial further clinical trials are needed to study this issue. Re-
from Iseli and colleagues where therapy-resistant cases garding acanthamoeba keratitis, 10 out of 11 cases
of melting corneas were treated with CXL. This time, healed, five of them with retreatment. Although this
every case was of infectious origin [7]. In this small co- meta-analysis reports good healing rates for acanth-
hort study, five patients with advanced corneal melt of amoeba keratitis, caution should be taken in monitoring
infectious origin were selected. Two patients presented a patients as almost half of them needed retreatment [55].
fungal keratitis, whereas the other three were infected More complicated clinical situations were also addressed
with Mycobacterium spp. pathogen. Each patient pre- in few reports using PACK-CXL to treat combined
sented a disease unresponsive to full topical and sys- pathological situations with infectious keratitis such as
temic microbicidal therapy. They received CXL with the bullous keratopathy or late-onset infections of a corneal
standard Dresden protocol technique: 3 mW/cm2 CXL graft [56, 57].
for 30 min [2, 7]. After surgery, the melting process was Riboflavin and ultraviolet light have been used for de-
halted in four out of five patients. The last patient cades to kill pathogens, in combination or separately
showed a persistent corneal melt caused by an immune (surface and water disinfection, blood sterilization prior
reaction without any remaining active pathogen. This to transfusion, etc.). Therefore, the microbicidal effect of
study not only confirmed the previous results from Sei- CXL can be explained through the effect of these two el-
ler and colleagues from the year 2000, but also intro- ements. First, ultraviolet (UV) light itself has a strong
duced the concept that CXL might be efficient when antimicrobial activity as it directly damages DNA and
treating corneal melts from an infectious origin. Subse- RNA in microbes such as bacteria, but also viruses, and
quently, further clinical trials on advanced melting inhibits microbes from replicating [58–61]. Riboflavin
corneas, one meta-analysis, and multiple animal experi- also possesses its own microbicidal effect. When it is
ments confirmed those initial results [20, 26–53]. photoactivated, it releases reactive oxygen species (ROS)
The next step after treating therapy-resistant cases of that directly interact with the nucleic acids and cell
advanced infectious keratitis was to treat early cases with membranes of the microbe [62, 63]. The combined effect
CXL. Thus in 2011, Makdoumi and colleagues from of UV-A light and riboflavin has been shown to be su-
Sweden proposed a prospective non-randomized clinical perior than their separate effect, with a 10-fold increased
trial to investigate the efficiency of CXL as first line ther- cytotoxicity when compared to UV-A alone [58, 64].
apy in bacterial keratitis [35]. They recruited 16 patients With the increasing number of publications on CXL
clinically diagnosed with infectious bacterial keratitis to treat infectious keratitis, a new terminology regarding
who had not received any previous antibiotic (topical or this specific use was proposed at the 9th International
systemic) treatment. All patients were treated with Cross-Linking Congress in 2013. It aims to distinguish
standard CXL as mentioned in the Dresden protocol (3 CXL for infections from CXL for corneal ectasia in order
mw/cm2 for 30 min with 0.1 % riboflavin) [1]. Of 16 pa- to avoid confusion in scientific publications and proto-
tients, 15 showed complete epithelial closure and all cols. The term PACK-CXL: Photo-Activated Chromo-
showed signs of improvement and reduction of inflam- phore for Keratitis – Corneal Cross-Linking was
matory response to the bacteria. Nevertheless, two pa- adopted for CXL when treating infectious keratitis [31].
tients needed additional antibiotic therapy to treat their
disease [35]. The Swedish team uncovered the microbici- Conclusion
dal effect of CXL in early bacterial keratitis as a first-line CXL was initially developed to stabilize keratoconus.
treatment in this trial. The Dresden protocol was developed after abundant la-
CXL has been shown to be an efficient treatment sta- boratory research including animal trials. This protocol
bilizing not only advanced melting corneal ulcers, but was tailored to only treat cornea with an ectatic disorder
also early infectious keratitis of bacterial origin over a and to protect the endothelium, avoiding any other com-
10-year period [26, 37, 41, 44–47, 54]. Photoactivated plication. As a safe protocol it was used when applying
chromophore for keratitis-corneal collagen cross-linking CXL to other diseases in order to avoid any non-
(PACK-CXL) has a very good healing rate regarding bac- desirable postoperative effect, and most studies continue
teria (average 88 %) as reported in a recent meta- using it for PACK-CXL as originally established. Our
analysis and most of the clinical trials are reporting a group recently demonstrated that an optimization of the
successful treatment rate when using PACK-CXL in protocol’s parameters allows reducing the treatment
combination with standard antimicrobial therapy [55]. time without impairing its killing rate on bacterial
Regarding fungal infections, healing rates are also good strains [43]. Already in the literature, some report suc-
(average 78 %). Some of those infections healed with an cessful treatment of accelerated protocols in humans
Tabibian et al. Eye and Vision (2016) 3:11 Page 4 of 5

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Competing interests
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The authors declare that they have no competing interests.
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