Review of the literature on the currently available evidence for the management of infectious keratitis with PACK-CXL | Archivos de la Sociedad Española de Oftalmología (English Edition)

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"apellidos" => "Rocha-de-Lossada" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "e" "identificador" => "aff0025" ] 1 => array:2 [ "etiqueta" => "f" "identificador" => "aff0030" ] 2 => array:2 [ "etiqueta" => "g" "identificador" => "aff0035" ] ] ] ] "afiliaciones" => array:7 [ 0 => array:3 [ "entidad" => "Complejo Hospitalario Universitario Torrecárdenas, Almería, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Hospital Regional Universitario de Málaga, Málaga, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Hospital Clínico San Carlos, Madrid, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Innova Ocular Clínica Dr. Soler, Elche, Alicante, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Departamento de Oftalmología (Qvision), Hospital Vithas Vírgen del Mar, Almería, Spain" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Hospital Universitario Vírgen de las Nieves, Granada, Spain" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Universidad de Sevilla, Departamento de Cirugía, Área de Oftalmología, Sevilla, Spain" "etiqueta" => "g" "identificador" => "aff0035" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Revisión de la literatura sobre la evidencia disponible actualmente para el manejo de las queratitis infecciosas con PACK-CXL" ] ] "textoCompleto" => "IntroductionInfectious keratitis (IK) is an important cause of visual loss worldwide, particularly in developing countries, and may be the result of minor ocular trauma combined with poor hygiene.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> Although the incidence rate in industrialised countries is significantly lower, IK can arise from contact lens wear, dry eye, recent ocular surgery or systemic immunosuppression.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> The use of broad-spectrum antibiotics (ATBs) can achieve microbiological eradication of the causative pathogens.<a class="elsevierStyleCrossRefs" href="#bib0005">1,3</a> The massive and widespread use of broad-spectrum ATBs has led to an increase in antimicrobial resistance (AMR).<a class="elsevierStyleCrossRefs" href="#bib0005">1,4</a> The progressive decrease in the effectiveness of ATBs leads to the appearance of complications such as corneal scarring,<a class="elsevierStyleCrossRef" href="#bib0025">5</a> endophthalmitis, corneal thinning or perforation,<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a> or the need for “hot” surgical therapeutic keratoplasties, such as penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty, which increase the rate of graft rejection.<a class="elsevierStyleCrossRefs" href="#bib0040">8–10</a> Therefore, there is a need for novel approaches to deal with IK, improving microbial eradication with fewer side effects such as corneal cross-linking (CXL).<a class="elsevierStyleCrossRefs" href="#bib0020">4,11</a> CXL is a technique developed in the 1990s for the treatment of corneal ectatic disorders such as keratoconus (KC). In 2003 the first article using CXL to stop the progression of KC was published.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In recent years, the use of CXL in IK has been proposed<a class="elsevierStyleCrossRefs" href="#bib0055">11,12</a> because of the ATM properties of the photoactivated chromophore (riboflavin [RB]) and ultraviolet (UV)-A light,<a class="elsevierStyleCrossRef" href="#bib0055">11</a> which could reduce pathogens and increase the resistance of corneal tissue to enzymatic degradation.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Thus, to distinguish the use of CXL for the treatment of IK from CXL for the management of progressive KC, the term PACK-CXL (photoactivated chromophore for corneal CXL in the treatment of IKs) was created at the ninth CXL congress in Dublin, Ireland, in 2013.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Its mechanism of action includes, among others, inhibition of microbial replication, RNA and DNA damage and direct damage of pathogen cell walls.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> The number of publications reporting on CXL treatment of IK is increasing, so that it could become a new alternative to standard ATB treatment of IK in the future.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> The aim of the present study is to conduct a literature review on the efficacy and safety outcomes of PACK-CXL in IC, based on the currently available scientific evidence.MethodologyThe literature search focused on retrieving comparative studies on the efficacy and safety of PACK-CXL for the treatment of IK. This search was conducted in the following databases: Cochrane Library, PubMed, EMBASE, Web of Science, Ovid MEDLINE and Scopus.Corneal cross-linkingCXL for the management of corneal ectasia was first published in 2003 by Wollensak et al. in order to stabilise the progression of KC.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In this technique, a combination of 370nmUV-A (320−400nm) and a photosensitising agent, RB, is used to increase the biomechanical stability and stiffness of the cornea.<a class="elsevierStyleCrossRefs" href="#bib0005">1,4</a> CXL has recently been used for the management of IK. The rationale for such use is based on the inherent strong ATM activity of UV light, which can directly damage DNA and RNA of various types of microorganisms.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In addition, reactive oxygen species released by photoactivated RB (these reactive species are generated when a photosensitiser, such as RB, is irradiated with UV-A in the presence of oxygen)<a class="elsevierStyleCrossRef" href="#bib0020">4</a> can directly affect DNA, cell membranes of micro-organisms, membrane-bound protein complexes, plasma membrane, lipids and nucleic acids, culminating in a powerful synergistic ATM action.<a class="elsevierStyleCrossRefs" href="#bib0005">1,4,11</a> Among the potential advantages of the application of UV-A light and RB over ATBs is the ability to decrease toxicity on the ocular surface and avoid adherence problems associated with the need for frequent topical treatment.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> The sum of these effects, together with increased corneal stiffness and resistance to proteolytic enzymatic digestion of corneal stromal collagen, have made CXL an attractive adjuvant in the treatment of IK.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>However, PACK-CXL is not commonly used in daily clinical practice due to uncertainty about its efficacy and safety.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> This is mainly attributed to the wide heterogeneity of the literature in relation to patient cohort, causative microorganisms, ulcer characteristics and severity, treatment protocol and the lack of large randomised clinical trials (RCTs) to support it.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Post-CXL neurotoxicityAnalysis of corneal nerve fibres by confocal microscopy has shown a loss of nerve fibres (immediate<a class="elsevierStyleCrossRef" href="#bib0075">15</a> or at one month<a class="elsevierStyleCrossRef" href="#bib0080">16</a>) from the subepithelial plexus, with apoptosis of mid-anterior stromal keratocytes, with basal restoration at 6 months post-CXL and no morphological changes at 1, 3 and 6 months post-CXL in the posterior stroma<a class="elsevierStyleCrossRefs" href="#bib0075">15,16</a> after standard CXL (CXL-S) and accelerated transepithelial CXL (CXL-TE-A) at 45mW/cm2.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Regeneration of the subepithelial plexus fibres occurred with rapid growth from the surrounding non-irradiated area between 2 and 3 months postoperatively,<a class="elsevierStyleCrossRefs" href="#bib0075">15,16</a> with a return to baseline corneal sensitivity values at 6–12 months postoperatively.<a class="elsevierStyleCrossRefs" href="#bib0075">15,16</a> However, confocal microscopy has not demonstrated loss of nerve fibres from the subepithelial plexus and mid-anterior stroma after CXL-TE at 3mW/cm2, probably due to the lower power used in the latter technique.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> Ultimately, nerve fibres regenerate completely 12 months after CXL, maintaining neurotrophism, corneal sensitivity and tear reflex.<a class="elsevierStyleCrossRefs" href="#bib0075">15,16</a>Effects of ultraviolet lightUV light with a wavelength (λ) of 200−400nm (nanometres) is a major stress factor for microorganisms and is used in multiple medical and non-medical applications for disinfection.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The ATM mechanism of action of UV light is DNA damage secondary to the direct absorption of photons by nucleic acids or the release of reactive oxygen species through a reaction with a photosensitising chemical substrate in the presence of oxygen. UV-C light with an λ of 200−280nm and UV-B light with anλ of 280−320nm can directly inactivate microorganisms by affecting the integrity of their DNA, while UV-A light with an λ of 320−400nm generates reactive oxygen species in the presence of a photosensitiser, RB, which can damage multiple targets within the same cell, including proteins and nucleic acids, thereby killing microorganisms.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> However, due to the paucity of adequate clinical data reported in the scientific literature, it is difficult to reach a consensus on an effective and safe dose of UV light that can be applied in an IK.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> An in vitro study highlighted that a single dose of 1.93mJ/cm2 of UV-C light was effective in inhibiting the growth of different bacteria, while a dose of 57.9mJ/cm2 did not compromise the feasability of cultured human corneal epithelial cells. In the knowledge of the authors, this is the only study that has evaluated the safety of UV ATM dose.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>Influence of PACK-CXL energy on microbial death ratePACK-CXL follows the Bunsen-Roscoe law, where an increase in fluence (J/cm2) does not necessarily imply a longer treatment duration, but could be achieved with a higher UV light irradiance (mW/cm2).<a class="elsevierStyleCrossRef" href="#bib0010">2</a> In the work of Kling et al.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> it was shown that the degree of bacterial death was dependent on the UV-A energy, but not on the irradiation time, as previously demonstrated in a work by Bäckman et al.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> Said authors observed that increasing the UV-A light irradiation energy to 16.2J/cm2 (corresponding to 18mW/cm2, for 15min or more) would probably kill 100% of Staphylococcus aureus-type bacteria at a concentration of 104 bacteria/mL.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> In addition, Kling et al. observed that the bacterial kill ratio with PACK-CXL was significantly reduced in larger irradiated volumes and was probably due to lower UV-A intensity in deeper layers and a higher absolute number of surviving bacteria.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> These authors also observed that higher treatment efficacy at higher volumes required higher UV energy (on average 3.8% per J/cm2). Interestingly, ATB-resistant strains had similar susceptibility in terms of bacterial death compared to non-resistant bacteria.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>It is important to note that the UV-A light dose delivered during a conventional CXL technique is 25 times higher than 216mJ/cm2, which is the value at which DNA strand breaks have been demonstrated in porcine corneal epithelial cells.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> It was therefore essential to make safety estimates of the corneal endothelium, lens and retina during and after CXL for higher UV light energies.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> These were initially done by concluding that corneas should be at least 400μ thick for an irradiance of 5.4J/cm2.<a class="elsevierStyleCrossRefs" href="#bib0010">2,18</a> However, new studies with higher UV energy, 7.2 and 18J/cm2, did not observe endothelial alterations.<a class="elsevierStyleCrossRefs" href="#bib0095">19,20</a> In addition, the concentration of RB in the endothelium has been shown to be 1.7 lower than the theoretical estimate, suggesting that the threshold for UV light damage previously defined for the corneal endothelium may be too conservative, which may allow for a larger energy margin when using PACK-CXL.<a class="elsevierStyleCrossRefs" href="#bib0105">21,22</a> In addition, infectious corneal ulcer areas are less transparent and thicker than normal corneal tissue, which would justify higher UV energy as long as the irradiation is focused exclusively on the ulcer.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>Treatment protocolsPACK-CXL standard and variations thereofAll studies in the systematic review by Marasini et al. applied similar treatment protocols and with a UV light dose intensity of 3mW/cm2.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> The mode of administration of 0.1% RB with 20% dextran was every 2min for a period of 30min and then every 5min for another 30min during UV-A irradiation.<a class="elsevierStyleCrossRefs" href="#bib0015">3,4,11,12</a> One study showed that an optimisation of the protocol parameters made it possible to reduce the treatment time without affecting the destruction rate of the bacterial strains.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> Price et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> evaluated the efficacy of UV-A exposure durations of 15, 30 and 45min in the presence of RB and reported that the procedure was safe, except in a previous herpes simplex virus infection, in which the infection recurred. The procedure was most effective in infections that did not extend deep into the cornea.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> Prajna et al. performed a CXL technique with a modified Dresden protocol, in which the epithelium around the ulcer was removed, followed by administration of UV-A light at 3mW/cm2,<a class="elsevierStyleCrossRef" href="#bib0060">12</a> and although the benefit of PACK-CXL for the primary treatment of moderate bacterial keratitis (BK) could not be confirmed, PACK-CXL may reduce culture positivity and complication rates.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Kasetsuwan et al. did not remove the epithelium because according to the authors epithelial defects already existed in the ulcers. These authors concluded that standard treatment with PACK-CXL provided no benefit over standard treatment in moderate to severe IK over a 30-day period.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>PACK-CXL acceleratedAccelerated PACK-CXL with modifications with respect to pathogen type in order to maintain an adequate microbial mortality rate could be as effective as the standard Dresden protocol (3mW/cm2 for 30min).<a class="elsevierStyleCrossRef" href="#bib0070">14</a> Tabibian et al. treated a case of Aureobasidium pullulans with PACK-CXL (9mW/cm2, for 10min), achieving total eradication of the infiltrate without topical ATB administration, in addition to complete closure of the corneal epithelium after 3 days.<a class="elsevierStyleCrossRef" href="#bib0125">25</a> Famose, in his work in dogs and cats, demonstrated in vitro that the antibacterial efficacy of PACK-CXL was preserved using an accelerated PACK-CXL protocol (30mW/cm2, for 3min), observing satisfactory results in cases of IK with corneal dissolution.<a class="elsevierStyleCrossRefs" href="#bib0130">26,27</a> Richoz et al. demonstrated in vitro that accelerated protocols of 18mW/cm2 for 5min and 36mW/cm2 for 2.5min had similar kill rates (approximately 93%) for Staphylococcus aureus and Pseudomonas aeruginosa compared to the Dresden protocol.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> In the work of Knyazer et al., PACK-CXL (accelerated protocol, 30mW/cm2 for 3min) was compared together with topical ATBs versus topical ATBs in monotherapy, in patients with BK.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> In addition, the treatment costs of both groups were analysed. The authors observed faster re-epithelialisation time, shorter hospitalisations, fewer follow-up visits and a significant reduction in the need for urgent PPQ in the PACK-CXL group, but no significant differences in cost.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> The authors consider that this treatment modality could have important implications for healthcare in the context of developing countries and raise it as an interesting avenue for future research.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> In this context of underdeveloped regions, which typically have a high prevalence of BK, it is worth considering the potential advantages of PACK-CXL, offering the alternative of a single, short course of therapy, given that it is very difficult to maintain a regimen of frequent visits and proper adherence to treatment in such a context.<a class="elsevierStyleCrossRef" href="#bib0065">13</a>PACK-CXL in bacterial infectionsSeveral studies have shown that PACK-CXL improved BK healing and blocked the progression of corneal thinning and perforation.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> Two systematic reviews of PACK-CXL have been published, which together included two RCTs.<a class="elsevierStyleCrossRefs" href="#bib0145">29,30</a> However, since these systematic reviews were published, other RCTs of PACK-CXL have been conducted. In a recent Cochrane review that focused primarily on the management of BK using papers comparing PACK-CXL in conjunction with standard therapy versus standard therapy in monotherapy.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> Two RCTs<a class="elsevierStyleCrossRefs" href="#bib0090">18,31</a> and one quasi-randomised controlled trial<a class="elsevierStyleCrossRef" href="#bib0160">32</a> were included. The studies included in the Cochrane review were highly variable with respect to outcome reporting and follow-up times.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> Clinical heterogeneity in reported outcomes made it difficult to compare data between RCTs. In addition, there was a wide range of follow-up times: from 14 to 120 days (time to healing).<a class="elsevierStyleCrossRef" href="#bib0140">28</a> The most significant limitation was that the studies provided insufficient information to assess cases of BK.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> Two of the 3 studies included keratitis of any etiology, but did not report results based on etiology.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> Ultimately, the authors of this Cochrane review concluded that there was insufficient evidence to support PACK-CXL combination therapy in conjunction with topical ATBs as a safe and effective treatment for BK.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> However, the 5 RCTs currently underway may provide better answers in the next update of this review.<a class="elsevierStyleCrossRefs" href="#bib0165">33–37</a>Papaionnaou et al.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> evaluated a total of 25 studies in their systematic review, 2 of which are studies previously included in the Cochrane review,<a class="elsevierStyleCrossRef" href="#bib0140">28</a> and concluded that PACK-CXL was more effective in cases of BK (87.2% cured out of 167 eyes), but again the evidence was low because of the high number of non-randomised studies included.<a class="elsevierStyleCrossRef" href="#bib0150">30</a>Makdoumi et al. conducted a prospective study (non-randomised clinical trial) with 16 patients with a clinical diagnosis of BK, in which none of them received ATB treatment prior to inclusion in the study, with the aim of investigating PACK-CXL as a primary therapy for BKs.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> This group observed that all eyes responded to PACK-CXL with improvement of symptoms and signs with respect to reduction of inflammation and healing of the epithelial defect in all cases.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> They observed that 16 patients with BK without prior ATB treatment underwent standard PACK-CXL (Dresden protocol; 3mW/cm2, 30min)<a class="elsevierStyleCrossRef" href="#bib0190">38</a>; 15 patients had complete epithelial closure and all showed signs of improvement and reduced inflammatory response to bacteria.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> Two participants required ATB treatment due to poor healing secondary to underlying systemic disease (diabetes with ocular complications) or recurrent epithelial defects.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> Ultimately, the authors concluded that PACK-CXL may have potential for the cure of patients with BK.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>The systematic review by Marasini et al. observed that 2 of 5 RCT (n=27), 2 of 4 non-RCT (n=25) and 17 of 22 case studies (n=58) evaluated PACK-CXL as a last chance to preserve corneal integrity in recalcitrant infections that did not respond to standard medical treatment.<a class="elsevierStyleCrossRef" href="#bib0020">4</a> However, despite the fact that CXL has shown efficacy in corneal ectasia in halting progression by improving the biomechanical stability of the uninfected cornea, the review by Marasini et al. observed that infected corneas that underwent PACK-CXL perforated or required enucleation in 15% of cases in RCTs, 0% of cases in included non-RCT studies and 12% of patients described in case series.<a class="elsevierStyleCrossRef" href="#bib0020">4</a>A meta-analysis by Ting et al. included 46 studies, of which 4 were RCTs, with 435 patients in total.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Compared to standard ATB monotherapy, adjuvant PACK-CXL in BC resulted in a shorter mean time to complete corneal healing and faster resolution of the infiltrate at both 1 week and 1 month, with no significant difference found in epithelial defect size, best corrected visual acuity and risk of adverse events.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> This review included 4 RCTs with 58 participants in the intervention group (PACK-CXL with standard TMJ therapy) and 57 participants in the control group (standard TMJ therapy).<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The majority of the studies focused on either KCs, fungal keratitis (FK) or a combination of both, and only one RCT included Acanthamoeba keratitis.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> No RCT examined the usefulness of PACK-CXL in viral keratitis.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> PACK-CXL was superior to ATM therapy in the resolution of infiltrate size at 7 days and at the end of follow-up (14–30 days).<a class="elsevierStyleCrossRefs" href="#bib0060">12,29</a> PACK-CXL did not reduce the risk of adverse events such as corneal perforation when compared to the ATM therapy alone group.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Three RCTs<a class="elsevierStyleCrossRefs" href="#bib0090">18,31,32</a> showed a similar or lower risk of adverse effects in the PACK-CXL group. However, Uddaraju et al.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> observed an opposite trend. Overall, the evidence was of very low quality, with insufficient sample size in the 4 RCTs to achieve sufficient power in terms of efficacy and safety outcomes.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Price et al.<a class="elsevierStyleCrossRef" href="#bib0120">24</a> and Hafezi and Randleman.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> previously estimated that 200–250 participants are needed to assess the efficacy of PACK-CXL, far short of the number of participants in the RCTs in this meta-analysis.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> The other limitation was the inconsistency in measurement and reporting of treatment outcomes among the 4 included RCTs, reporting 8 different outcomes.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> In addition, the risk of adverse events was the only outcome that was systematically examined across the 4 RCTs.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Ultimately, this meta-analysis demonstrates that adjuvant PACK-CXL accelerates healing of IK compared to ATM therapy alone, with low quality evidence. Therefore, it shows that more high-quality and adequately powered RCTs are needed to fully determine the therapeutic effect of PACK-CXL.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>Prajna et al. noted that no benefit of adjuvant CXL in the primary treatment of BKs could be demonstrated.<a class="elsevierStyleCrossRef" href="#bib0060">12</a> However, they did observe that the CXL group was less likely to have positive cultures at 24h than patients in the group given topical moxifloxacin (0.5%).<a class="elsevierStyleCrossRef" href="#bib0060">12</a> Bamdad et al. demonstrated that patients who received CXL and ATB, relative to those in the ATB monotherapy group (topical moxifloxacin 0.5%/h), had a smaller area of epithelial defect, a smaller area of infiltration and a shorter mean duration of treatment.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>In the work of Kasetsuwan et al. they observed that standard combined treatment with PACK-CXL in moderate to severe KC and FK did not provide any benefit over standard treatment alone.<a class="elsevierStyleCrossRef" href="#bib0015">3</a> No significant differences in the size of infiltrates or epithelial defects were observed.<a class="elsevierStyleCrossRef" href="#bib0015">3</a>Achiron et al. in their study compared PACK-CXL in combination with standard ATB therapy (26 eyes) to standard ATB therapy alone (21 eyes) in patients with moderate and severe KCB. The authors demonstrated that the combined treatment reduces healing time, improves final visual acuity (VA) and reduces the need for tectonic keratoplasty.<a class="elsevierStyleCrossRef" href="#bib0205">41</a> The authors observed that patients in the first group had more favourable results in terms of number of tectonic grafts (0% in the combined group compared to 33.3% in the standard ATB alone group), better final uncorrected VA (mean difference, compared to the standard ATB alone group, of 0.57 logMAR) and better final corrected VA (mean difference, compared to the standard ATB alone group, of 0.7 logMAR) and shorter re-epithelialisation time (mean difference of 9.63 days).<a class="elsevierStyleCrossRef" href="#bib0205">41</a>PACK-CXL in Acanthamoeba infectionsFour in vitro studies evaluated the impact of UV radiation on Acanthamoeba isolated from corneal ulcers, and reported that the method was ineffective in inhibiting their proliferation,<a class="elsevierStyleCrossRefs" href="#bib0210">42–45</a> while the same treatment, at similar doses, was shown to be effective in some patients.<a class="elsevierStyleCrossRefs" href="#bib0230">46–48</a> However, in the meta-analysis by Ting et al. the evidence on the use of PACK-CXL in Acanthamoeba keratitis and mixed keratitis (MK) was insufficient.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>PACK-CXL in fungal infectionsManagement of fungal keratitis (FK) is challenging and recurrence of infection can be observed even after keratoplasty (KP).<a class="elsevierStyleCrossRef" href="#bib0245">49</a> Deep corneal vascularisation is a high-risk factor affecting graft survival and optical Pk is often necessary after “warm” Pk to obtain satisfactory visual rehabilitation.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> CXL in Boston keratoprosthesis donor corneas results in a lower incidence of corneal dissolution,<a class="elsevierStyleCrossRef" href="#bib0245">49</a> which may be beneficial in preventing deep vascularisation<a class="elsevierStyleCrossRef" href="#bib0245">49</a> and may alter corneal permeability to drugs.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> Thus, the authors of this study conclude that CXL-treated donor corneas could help reduce the incidence of graft reinfection after keratoplasty in FK.<a class="elsevierStyleCrossRef" href="#bib0245">49</a>The study by Uddaraju et al.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> included severe and refractory FK with involvement of the posterior two-thirds of the cornea and unresponsive to standard antifungal therapy during the previous 2 weeks, so the findings could be confounded by the difference in the initial severity of FK where the PACK-CXL group was much worse than the single ATM therapy group.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> Based on these findings, the authors advise against the use of PACK-CXL in severe deep FK.<a class="elsevierStyleCrossRef" href="#bib0195">39</a>The study by Prajna et al. aims to determine if there is any benefit of PACK-CXL in filamentous FK and compares topical natamycin 5% versus topical amphotericin 0.15%.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> Four groups were randomised: topical natamycin 5%, natamycin 5%+PACK-CXL, amphotericin 0.15% and amphotericin 0.15%+PACK-CXL.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> The results obtained were that patients assigned to the PACK-CXL group, regardless of whether they received natamycin or topical amphotericin, were 1.32 more likely to have culture positivity at 24h, without being statistically significant, and the best corrected VA was 0.22logMAR worse on average at 3 weeks and 0.32logMAR worse at 3 months, among those who received PACK-CXL. No differences were observed in the size of infiltrates and/or scarring, nor in the percentage of adverse events between the groups.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> Ultimately, there appears to be no benefit of adjuvant PACK-CXL in the treatment of filamentous FK, and may even result in a decrease in VA in the PACK-CXL group.<a class="elsevierStyleCrossRef" href="#bib0250">50</a>The Cross-Linking Assisted Infection Reduction (CLAIR) RCT observed no benefit of PACK-CXL in the primary management of filamentous FK at 3 months.<a class="elsevierStyleCrossRef" href="#bib0250">50</a> At 12-month follow-up of the CLAIR trial,<a class="elsevierStyleCrossRef" href="#bib0255">51</a> the best corrected VA was 1.8logMAR worse in the PACK-CXL group. No difference in VA was observed between those randomised to topical amphotericin 0.15% versus the topical natamycin 5% group, regardless of whether or not they underwent PACK-CXL, and no difference in ulcer infiltrate and/or scar size was observed between those who received PACK-CXL compared to those who did not.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> There were 10 patients with full-thickness corneal perforation, 4 in the PACK-CXL group and 6 in the topical medication monotherapy group.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> A total of 21 patients ended up in keratoplasty, 11 patients in the PACK-CXL group and 10 patients in the medication only group.<a class="elsevierStyleCrossRef" href="#bib0255">51</a> In summary, at 12 months there was no benefit of PACK-CXL as an adjuvant in the treatment of filamentous FK, in terms of VA, scar size or complications, including perforation and QP.Bamdad et al. observed in their work that out of 9 patients with FK refractory to conventional treatment, 4 (2 cases caused by Aspergillus and 2 by Fusarium) had a good response to PACK-CXL, with a mean time to complete epithelialisation and a mean time to resolution of stromal infiltration of 14.25±2.38 and 22.5±7.29 days, respectively.<a class="elsevierStyleCrossRef" href="#bib0260">52</a> There were no statistically significant differences between the responder and non-responder groups with respect to mean depth of infiltration and mean ulcer size.<a class="elsevierStyleCrossRef" href="#bib0260">52</a> The authors conclude that PACK-CXL could be added to the therapeutic arsenal of antimicrobial agents for the management of severe and refractory cases of FK.<a class="elsevierStyleCrossRef" href="#bib0260">52</a>Recently, a phase 3 RCT has been published, where participants, with BK, FK or MF, were randomised to 2 groups (PACK-CXL vs. ATM therapy).<a class="elsevierStyleCrossRef" href="#bib0265">53</a> In this work, it was observed that the success rate (defined as complete resolution of signs of infection) in the PACK-CXL group (n=18) was 88.9% (16/18 patients), and 90.5% (19/21 patients) in the ATM therapy group (n=21).<a class="elsevierStyleCrossRef" href="#bib0265">53</a> The authors conclude that PACK-CXL may be an alternative to ATM drugs for the first-line, stand-alone treatment of early to moderate BK, FK or MK.<a class="elsevierStyleCrossRef" href="#bib0265">53</a>PACK-CXL in infectious keratitis after penetrating keratoplastyThe incidence of post-PPK IK varies between 1.76%–12.1%, with a treatment failure rate in PPKs of 26%–57% (as opposed to a 10% failure rate in non-PPK IK).<a class="elsevierStyleCrossRef" href="#bib0270">54</a> IKs may account for 5.1%–32.3% of all indications for PPK, depending on the series.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Due to the long-term use of topical steroids, Staphylococcus and Candida are the main causes of post-PPK IKs.<a class="elsevierStyleCrossRef" href="#bib0270">54</a> In the work of Uzman et al. a higher, but not statistically significant, rate of resolution of BK and QF infiltrates was observed in the PACK-CXL group combined with TMJ therapy (83.3%) compared to the control group, which received TMJ therapy alone (68.2%).<a class="elsevierStyleCrossRef" href="#bib0270">54</a> In addition, they observed that the infiltrates did not resolve after PACK-CXL in 2 patients with BK and 1 patient with FK, both of whom had full-thickness corneal stroma involvement.<a class="elsevierStyleCrossRef" href="#bib0270">54</a> The results of Uzman et al. show that the depth of the infiltrate is more important than the type of pathogen, with a 25% resolution rate observed in cases of total corneal involvement with endothelial plaque,<a class="elsevierStyleCrossRef" href="#bib0270">54</a> so that the response to treatment with PACK-CXL seems to be better in early IK, when the infection only affects the superficial layers of the corneal stroma<a class="elsevierStyleCrossRef" href="#bib0270">54</a>; this could be explained because the effect of CXL with Dresden protocol is limited to the anterior 300μ of the stroma.<a class="elsevierStyleCrossRef" href="#bib0270">54</a> Ultimately, PACK-CXL demonstrated a shorter healing time and a higher proportion of patients with at least 2 lines of visual improvement compared to the group treated with antimicrobial therapy alone.<a class="elsevierStyleCrossRef" href="#bib0270">54</a>Infectious keratitis post-CXLAlthough CXL has been used for the management of IK, these infections can occur postoperatively with this same technique.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> Among the main causes described are the presence of an epithelial defect, the use of contact lenses and/or topical steroids in the immediate postoperative period.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> In the case of IK post-CXL, microbial invasion is likely to occur during the postoperative period rather than during surgery, as this technique not only damages keratocytes but also kills bacteria and fungi.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> In an open-label comparative clinical trial, Tzamalis et al. found that delaying the use of topical steroids until the epithelium healed reduced the likelihood of infection.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> In the work of Khoo et al. more than 70% of patients had worn contact lenses within one month prior to infection.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> However, due to the study design it could not be determined whether the use of a contact lens, a topical steroid or their combination leads to an increase in infection.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> The CXL epi-off technique is itself a predisposing risk factor for IK because of the epithelial defect resulting from the technique, which can take 2–5 days to heal and is an important entry point for microorganisms.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> The organisms described as causing post-CXL IK range from bacteria to herpes simplex virus, fungi and even Acanthamoeba.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> In the work of Khoo et al. 42% of the causative organisms were coagulase negative staphylococci.<a class="elsevierStyleCrossRef" href="#bib0110">22</a> While it is true that CXL may have ATM activity, it may also alter the normal ocular flora, and thus secondarily increase the risk of infection, especially when the corneal epithelium is compromised.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>ConclusionsPACK-CXL could serve as a useful therapeutic arsenal to complete healing and reduce the size of the infiltrate in IK<a class="elsevierStyleCrossRef" href="#bib0005">1</a> but we should note that, to our knowledge, there are no studies (including in vitro studies) that have evaluated the safety of the treatment with respect to its potential genotoxicity, i.e. its ability to induce mutations in cellular genetic information.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Adjustments of CXL treatment parameters, as well as the duration of irradiation and energy used, could help increase the efficacy of PACK-CXL depending on the type of pathogen.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> The timing of initiating PACK-CXL could be chosen according to the clinical evolution of the patients, but it is recommended, following current evidence, that PACK-CXL be performed one week after the start of medical treatment in non-responder patients.<a class="elsevierStyleCrossRef" href="#bib0270">54</a>The authors of the Cochrane review concluded that there was insufficient evidence to support PACK-CXL combined therapy with topical ATBs as a safe and effective treatment for BK.<a class="elsevierStyleCrossRef" href="#bib0140">28</a> However, Papaionnaou et al.<a class="elsevierStyleCrossRef" href="#bib0150">30</a> and Ting et al.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> concluded that PACK-CXL was more effective in cases of BK (87.2% cured out of 167 eyes)<a class="elsevierStyleCrossRef" href="#bib0150">30</a> and had a shorter mean time to complete corneal healing and faster resolution of the infiltrate,<a class="elsevierStyleCrossRef" href="#bib0005">1</a> although the evidence was low due to the high number of non-randomised studies included.<a class="elsevierStyleCrossRefs" href="#bib0005">1,30</a>The SCUT II study protocol has recently been published, where the authors hope that the results of this work will provide evidence of the efficacy of PACK-CXL and early steroids as adjunctive treatments in KC.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> The authors anticipate that these therapies will improve outcomes such as VA, while reducing the rate of complications such as corneal perforation or the need for therapeutic PK.<a class="elsevierStyleCrossRef" href="#bib0025">5</a>Current evidence on the use of PACK-CXL is insufficient for the recommendation of this technique in Acanthamoeba keratitis and MK.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> Furthermore, in viral keratitis, PACK-CXL is contraindicated because of the possibility of exacerbating or activating herpes simplex virus infection.<a class="elsevierStyleCrossRefs" href="#bib0005">1,24,55</a>Following the conclusions of the CLAIR study, there appears to be no benefit of adjuvant PACK-CXL in the treatment of filamentous FK either at 3 or 12 months follow-up, and it may even produce a decrease in VA in the PACK-CXL group.<a class="elsevierStyleCrossRefs" href="#bib0250">50,51</a> However, Bamdad et al. recommend the use of PACK-CXL in cases of refractory FK to avoid emergency PCI.<a class="elsevierStyleCrossRef" href="#bib0260">52</a>In summary, the current evidence on the effectiveness of PACK-CXL for the management of IK appears to be low, clinically heterogeneous in terms of outcomes<a class="elsevierStyleCrossRef" href="#bib0140">28</a> and with questionable safety in certain etiologies. Currently, there are 5 ongoing RCTs<a class="elsevierStyleCrossRefs" href="#bib0165">33–37</a> with 1136 participants, which will hopefully provide more specific and clarifying answers.Conflicts of interestNo conflicts of interest were declared by the authors." "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1751653" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1542804" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1751654" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1542805" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methodology" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Corneal cross-linking" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Post-CXL neurotoxicity" ] ] ] 7 => array:2 [ "identificador" => "sec0025" "titulo" => "Effects of ultraviolet light" ] 8 => array:2 [ "identificador" => "sec0030" "titulo" => "Influence of PACK-CXL energy on microbial death rate" ] 9 => array:3 [ "identificador" => "sec0035" "titulo" => "Treatment protocols" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "PACK-CXL standard and variations thereof" ] 1 => array:2 [ "identificador" => "sec0045" "titulo" => "PACK-CXL accelerated" ] 2 => array:2 [ "identificador" => "sec0050" "titulo" => "PACK-CXL in bacterial infections" ] 3 => array:2 [ "identificador" => "sec0055" "titulo" => "PACK-CXL in Acanthamoeba infections" ] 4 => array:2 [ "identificador" => "sec0060" "titulo" => "PACK-CXL in fungal infections" ] 5 => array:2 [ "identificador" => "sec0065" "titulo" => "PACK-CXL in infectious keratitis after penetrating keratoplasty" ] 6 => array:2 [ "identificador" => "sec0070" "titulo" => "Infectious keratitis post-CXL" ] ] ] 10 => array:2 [ "identificador" => "sec0075" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0080" "titulo" => "Conflicts of interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-10-30" "fechaAceptado" => "2022-02-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1542804" "palabras" => array:4 [ 0 => "Infectious keratitis" 1 => "Corneal cross-linking" 2 => "PACK-CXL" 3 => "Corneal ulcer" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1542805" "palabras" => array:4 [ 0 => "Queratitis infecciosas" 1 => "Cross-linking corneal" 2 => "PACK-CXL" 3 => "Úlcera corneal" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Infectious keratitis (IK) is one of the most common causes of monocular blindness worldwide, especially in developing countries and may account for 5.1%–32.3% of all indications for penetrating keratoplasty (PK). However, performing a therapeutic PK on a “hot eye” is associated with a higher incidence of IK recurrence and graft rejection. Standard treatment includes antimicrobials (ATM) and, once the causative pathogen has been identified, must be continued with targeted treatment, depending on antibiogram sensitivity. However, appearance of multiresistant strains to ATM is progressively increasing at an alarming rate. Besides that, the diversity of the causative microorganisms (bacteria, fungi, parasites, viruses) may hinder the clinical diagnosis and secondarily the proper treatment from the beginning. It is estimated that only 50% of eyes will have a good visual result if the correct therapy is delayed. All these factors make the identification of alternatives to ATM treatment of paramount importance. Due to the ATM properties of photoactivated chromophore (riboflavin, RB) and ultraviolet (UV) light of wavelength (λ) 200–400 nanometers (nm), used in multiple medical and non-medical applications for disinfection, photoactivated chromophore for corneal cross-linking (CXL) of IK (PACK-CXL), as an addition to the therapeutic arsenal for the management of IK has been proposed. It must be differentiated from CXL used for the management of progressive keratoconus (KC). The objective of this review is to update the available evidence on the efficacy and safety of PACK-CXL in IKs." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Las queratitis infecciosas (QI) es una de las causas más comunes de ceguera a nivel mundial, especialmente en países en vías de desarrollo y puede llegar a representar del 5.1% al 32.3% de todas las indicaciones de queratoplastia penetrante (QPP). Sin embargo, realizar una queratoplastia terapéutica en “caliente” está asociado con una mayor incidencia de recurrencia de la QI y rechazo del injerto. El tratamiento estándar incluye antimicrobianos (ATM) de amplio espectro y, una vez identificado el patógeno causante y el antibiograma, continuar con un tratamiento dirigido, según la sensibilidad del germen. La aparición de cepas multirresistentes a los ATM está aumentando progresivamente a un ritmo alarmante en los últimos tiempos. Asimismo, la diversidad de los microorganismos causantes (bacterias, hongos, parásitos, virus) dificultan en ocasiones la realización de diagnóstico clínico correcto, retrasando en inicio de un tratamiento efectivo. Se estima que sólo un 50% de los ojos tendrá un buen resultado visual si se retrasa la terapia. En definitiva, todos estos factores hacen que sea muy importante la identificación de alternativas al tratamiento ATM. Por las propiedades ATM del cromóforo fotoactivado (riboflavina, RB) y la luz ultravioleta (UV) de longitud de onda (λ) 200−400 nanómetros (nm), utilizada en múltiples aplicaciones médicas y no médicas para la desinfección, se ha propuesto el cromóforo fotoactivado para el cross-linking (CXL) corneal en el tratamiento de las QI (por sus siglas en inglés, PACK-CXL), como una herramienta adicional en el arsenal terapéutico de las QI. Debe diferenciarse del CXL empleado para el manejo del queratocono (QC) progresivo. El objetivo de esta revisión es actualizar la evidencia disponible sobre la eficacia y seguridad de PACK-CXL en las QI." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Hamida Abdelkader SM, Rodríguez Calvo-de-Mora M, Gegúndez-Fernández JA, Soler-Ferrández FL, Rocha-de-Lossada C. Revisión de la literatura sobre la evidencia disponible actualmente para el manejo de las queratitis infecciosas con PACK-CXL. 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Review of the literature on the currently available evidence for the management of infectious keratitis with PACK-CXL

Revisión de la literatura sobre la evidencia disponible actualmente para el manejo de las queratitis infecciosas con PACK-CXL

S.M. Hamida Abdelkadera,

Corresponding author

smha.ard@gmail.com

Corresponding author.

, M. Rodríguez Calvo-de-Morab, J.A. Gegúndez-Fernándezc, F.L. Soler-Ferrándezd, C. Rocha-de-Lossadae,f,g

a Complejo Hospitalario Universitario Torrecárdenas, Almería, Spain

b Hospital Regional Universitario de Málaga, Málaga, Spain

c Hospital Clínico San Carlos, Madrid, Spain

d Innova Ocular Clínica Dr. Soler, Elche, Alicante, Spain

e Departamento de Oftalmología (Qvision), Hospital Vithas Vírgen del Mar, Almería, Spain

f Hospital Universitario Vírgen de las Nieves, Granada, Spain

g Universidad de Sevilla, Departamento de Cirugía, Área de Oftalmología, Sevilla, Spain

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    "titulo" => "Review of the literature on the currently available evidence for the management of infectious keratitis with PACK-CXL"
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        "titulo" => "Revisi&#243;n de la literatura sobre la evidencia disponible actualmente para el manejo de las queratitis infecciosas con PACK-CXL"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Infectious keratitis &#40;IK&#41; is an important cause of visual loss worldwide&#44; particularly in developing countries&#44; and may be the result of minor ocular trauma combined with poor hygiene&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> Although the incidence rate in industrialised countries is significantly lower&#44; IK can arise from contact lens wear&#44; dry eye&#44; recent ocular surgery or systemic immunosuppression&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> The use of broad-spectrum antibiotics &#40;ATBs&#41; can achieve microbiological eradication of the causative pathogens&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3</span></a> The massive and widespread use of broad-spectrum ATBs has led to an increase in antimicrobial resistance &#40;AMR&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4</span></a> The progressive decrease in the effectiveness of ATBs leads to the appearance of complications such as corneal scarring&#44;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> endophthalmitis&#44; corneal thinning or perforation&#44;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> or the need for &#8220;hot&#8221; surgical therapeutic keratoplasties&#44; such as penetrating keratoplasty &#40;PK&#41; or deep anterior lamellar keratoplasty&#44; which increase the rate of graft rejection&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;10</span></a> Therefore&#44; there is a need for novel approaches to deal with IK&#44; improving microbial eradication with fewer side effects such as corneal cross-linking &#40;CXL&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;11</span></a> CXL is a technique developed in the 1990s for the treatment of corneal ectatic disorders such as keratoconus &#40;KC&#41;&#46; In 2003 the first article using CXL to stop the progression of KC was published&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In recent years&#44; the use of CXL in IK has been proposed<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> because of the ATM properties of the photoactivated chromophore &#40;riboflavin &#91;RB&#93;&#41; and ultraviolet &#40;UV&#41;-A light&#44;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> which could reduce pathogens and increase the resistance of corneal tissue to enzymatic degradation&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Thus&#44; to distinguish the use of CXL for the treatment of IK from CXL for the management of progressive KC&#44; the term PACK-CXL &#40;photoactivated chromophore for corneal CXL in the treatment of IKs&#41; was created at the ninth CXL congress in Dublin&#44; Ireland&#44; in 2013&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Its mechanism of action includes&#44; among others&#44; inhibition of microbial replication&#44; RNA and DNA damage and direct damage of pathogen cell walls&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The number of publications reporting on CXL treatment of IK is increasing&#44; so that it could become a new alternative to standard ATB treatment of IK in the future&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The aim of the present study is to conduct a literature review on the efficacy and safety outcomes of PACK-CXL in IC&#44; based on the currently available scientific evidence&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methodology</span><p id="par0010" class="elsevierStylePara elsevierViewall">The literature search focused on retrieving comparative studies on the efficacy and safety of PACK-CXL for the treatment of IK&#46; This search was conducted in the following databases&#58; Cochrane Library&#44; PubMed&#44; EMBASE&#44; Web of Science&#44; Ovid MEDLINE and Scopus&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Corneal cross-linking</span><p id="par0015" class="elsevierStylePara elsevierViewall">CXL for the management of corneal ectasia was first published in 2003 by Wollensak et al&#46; in order to stabilise the progression of KC&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In this technique&#44; a combination of 370<span class="elsevierStyleHsp" style=""></span>nm<span class="elsevierStyleHsp" style=""></span>UV-A &#40;320&#8722;400<span class="elsevierStyleHsp" style=""></span>nm&#41; and a photosensitising agent&#44; RB&#44; is used to increase the biomechanical stability and stiffness of the cornea&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4</span></a> CXL has recently been used for the management of IK&#46; The rationale for such use is based on the inherent strong ATM activity of UV light&#44; which can directly damage DNA and RNA of various types of microorganisms&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In addition&#44; reactive oxygen species released by photoactivated RB &#40;these reactive species are generated when a photosensitiser&#44; such as RB&#44; is irradiated with UV-A in the presence of oxygen&#41;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> can directly affect DNA&#44; cell membranes of micro-organisms&#44; membrane-bound protein complexes&#44; plasma membrane&#44; lipids and nucleic acids&#44; culminating in a powerful synergistic ATM action&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;11</span></a> Among the potential advantages of the application of UV-A light and RB over ATBs is the ability to decrease toxicity on the ocular surface and avoid adherence problems associated with the need for frequent topical treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> The sum of these effects&#44; together with increased corneal stiffness and resistance to proteolytic enzymatic digestion of corneal stromal collagen&#44; have made CXL an attractive adjuvant in the treatment of IK&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">However&#44; PACK-CXL is not commonly used in daily clinical practice due to uncertainty about its efficacy and safety&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> This is mainly attributed to the wide heterogeneity of the literature in relation to patient cohort&#44; causative microorganisms&#44; ulcer characteristics and severity&#44; treatment protocol and the lack of large randomised clinical trials &#40;RCTs&#41; to support it&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Post-CXL neurotoxicity</span><p id="par0025" class="elsevierStylePara elsevierViewall">Analysis of corneal nerve fibres by confocal microscopy has shown a loss of nerve fibres &#40;immediate<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> or at one month<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a>&#41; from the subepithelial plexus&#44; with apoptosis of mid-anterior stromal keratocytes&#44; with basal restoration at 6 months post-CXL and no morphological changes at 1&#44; 3 and 6 months post-CXL in the posterior stroma<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> after standard CXL &#40;CXL-S&#41; and accelerated transepithelial CXL &#40;CXL-TE-A&#41; at 45<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Regeneration of the subepithelial plexus fibres occurred with rapid growth from the surrounding non-irradiated area between 2 and 3 months postoperatively&#44;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> with a return to baseline corneal sensitivity values at 6&#8211;12 months postoperatively&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> However&#44; confocal microscopy has not demonstrated loss of nerve fibres from the subepithelial plexus and mid-anterior stroma after CXL-TE at 3<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span>&#44; probably due to the lower power used in the latter technique&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Ultimately&#44; nerve fibres regenerate completely 12 months after CXL&#44; maintaining neurotrophism&#44; corneal sensitivity and tear reflex&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a></p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Effects of ultraviolet light</span><p id="par0030" class="elsevierStylePara elsevierViewall">UV light with a wavelength &#40;&#955;&#41; of 200&#8722;400<span class="elsevierStyleHsp" style=""></span>nm &#40;nanometres&#41; is a major stress factor for microorganisms and is used in multiple medical and non-medical applications for disinfection&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The ATM mechanism of action of UV light is DNA damage secondary to the direct absorption of photons by nucleic acids or the release of reactive oxygen species through a reaction with a photosensitising chemical substrate in the presence of oxygen&#46; UV-C light with an &#955; of 200&#8722;280<span class="elsevierStyleHsp" style=""></span>nm and UV-B light with an&#955; of 280&#8722;320<span class="elsevierStyleHsp" style=""></span>nm can directly inactivate microorganisms by affecting the integrity of their DNA&#44; while UV-A light with an &#955; of 320&#8722;400<span class="elsevierStyleHsp" style=""></span>nm generates reactive oxygen species in the presence of a photosensitiser&#44; RB&#44; which can damage multiple targets within the same cell&#44; including proteins and nucleic acids&#44; thereby killing microorganisms&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> However&#44; due to the paucity of adequate clinical data reported in the scientific literature&#44; it is difficult to reach a consensus on an effective and safe dose of UV light that can be applied in an IK&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> An <span class="elsevierStyleItalic">in vitro</span> study highlighted that a single dose of 1&#46;93<span class="elsevierStyleHsp" style=""></span>mJ&#47;cm<span class="elsevierStyleSup">2</span> of UV-C light was effective in inhibiting the growth of different bacteria&#44; while a dose of 57&#46;9<span class="elsevierStyleHsp" style=""></span>mJ&#47;cm<span class="elsevierStyleSup">2</span> did not compromise the feasability of cultured human corneal epithelial cells&#46; In the knowledge of the authors&#44; this is the only study that has evaluated the safety of UV ATM dose&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Influence of PACK-CXL energy on microbial death rate</span><p id="par0035" class="elsevierStylePara elsevierViewall">PACK-CXL follows the Bunsen-Roscoe law&#44; where an increase in fluence &#40;J&#47;cm<span class="elsevierStyleSup">2</span>&#41; does not necessarily imply a longer treatment duration&#44; but could be achieved with a higher UV light irradiance &#40;mW&#47;cm<span class="elsevierStyleSup">2</span>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In the work of Kling et al&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> it was shown that the degree of bacterial death was dependent on the UV-A energy&#44; but not on the irradiation time&#44; as previously demonstrated in a work by B&#228;ckman et al&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Said authors observed that increasing the UV-A light irradiation energy to 16&#46;2<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span> &#40;corresponding to 18<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span>&#44; for 15<span class="elsevierStyleHsp" style=""></span>min or more&#41; would probably kill 100&#37; of <span class="elsevierStyleItalic">Staphylococcus aureus-type</span> bacteria at a concentration of 10<span class="elsevierStyleSup">4</span> bacteria&#47;mL&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In addition&#44; Kling et al&#46; observed that the bacterial kill ratio with PACK-CXL was significantly reduced in larger irradiated volumes and was probably due to lower UV-A intensity in deeper layers and a higher absolute number of surviving bacteria&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> These authors also observed that higher treatment efficacy at higher volumes required higher UV energy &#40;on average 3&#46;8&#37; per J&#47;cm<span class="elsevierStyleSup">2</span>&#41;&#46; Interestingly&#44; ATB-resistant strains had similar susceptibility in terms of bacterial death compared to non-resistant bacteria&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">It is important to note that the UV-A light dose delivered during a conventional CXL technique is 25 times higher than 216<span class="elsevierStyleHsp" style=""></span>mJ&#47;cm<span class="elsevierStyleSup">2</span>&#44; which is the value at which DNA strand breaks have been demonstrated in porcine corneal epithelial cells&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> It was therefore essential to make safety estimates of the corneal endothelium&#44; lens and retina during and after CXL for higher UV light energies&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> These were initially done by concluding that corneas should be at least 400<span class="elsevierStyleHsp" style=""></span>&#956; thick for an irradiance of 5&#46;4<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;18</span></a> However&#44; new studies with higher UV energy&#44; 7&#46;2 and 18<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span>&#44; did not observe endothelial alterations&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a> In addition&#44; the concentration of RB in the endothelium has been shown to be 1&#46;7 lower than the theoretical estimate&#44; suggesting that the threshold for UV light damage previously defined for the corneal endothelium may be too conservative&#44; which may allow for a larger energy margin when using PACK-CXL&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;22</span></a> In addition&#44; infectious corneal ulcer areas are less transparent and thicker than normal corneal tissue&#44; which would justify higher UV energy as long as the irradiation is focused exclusively on the ulcer&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Treatment protocols</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">PACK-CXL standard and variations thereof</span><p id="par0045" class="elsevierStylePara elsevierViewall">All studies in the systematic review by Marasini et al&#46; applied similar treatment protocols and with a UV light dose intensity of 3<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> The mode of administration of 0&#46;1&#37; RB with 20&#37; dextran was every 2<span class="elsevierStyleHsp" style=""></span>min for a period of 30<span class="elsevierStyleHsp" style=""></span>min and then every 5<span class="elsevierStyleHsp" style=""></span>min for another 30<span class="elsevierStyleHsp" style=""></span>min during UV-A irradiation&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;4&#44;11&#44;12</span></a> One study showed that an optimisation of the protocol parameters made it possible to reduce the treatment time without affecting the destruction rate of the bacterial strains&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Price et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> evaluated the efficacy of UV-A exposure durations of 15&#44; 30 and 45<span class="elsevierStyleHsp" style=""></span>min in the presence of RB and reported that the procedure was safe&#44; except in a previous herpes simplex virus infection&#44; in which the infection recurred&#46; The procedure was most effective in infections that did not extend deep into the cornea&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Prajna et al&#46; performed a CXL technique with a modified Dresden protocol&#44; in which the epithelium around the ulcer was removed&#44; followed by administration of UV-A light at 3<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> and although the benefit of PACK-CXL for the primary treatment of moderate bacterial keratitis &#40;BK&#41; could not be confirmed&#44; PACK-CXL may reduce culture positivity and complication rates&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Kasetsuwan et al&#46; did not remove the epithelium because according to the authors epithelial defects already existed in the ulcers&#46; These authors concluded that standard treatment with PACK-CXL provided no benefit over standard treatment in moderate to severe IK over a 30-day period&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">PACK-CXL accelerated</span><p id="par0050" class="elsevierStylePara elsevierViewall">Accelerated PACK-CXL with modifications with respect to pathogen type in order to maintain an adequate microbial mortality rate could be as effective as the standard Dresden protocol &#40;3<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span> for 30<span class="elsevierStyleHsp" style=""></span>min&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Tabibian et al&#46; treated a case of <span class="elsevierStyleItalic">Aureobasidium pullulans</span> with PACK-CXL &#40;9<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span>&#44; for 10<span class="elsevierStyleHsp" style=""></span>min&#41;&#44; achieving total eradication of the infiltrate without topical ATB administration&#44; in addition to complete closure of the corneal epithelium after 3 days&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Famose&#44; in his work in dogs and cats&#44; demonstrated <span class="elsevierStyleItalic">in vitro</span> that the antibacterial efficacy of PACK-CXL was preserved using an accelerated PACK-CXL protocol &#40;30<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span>&#44; for 3<span class="elsevierStyleHsp" style=""></span>min&#41;&#44; observing satisfactory results in cases of IK with corneal dissolution&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> Richoz et al&#46; demonstrated <span class="elsevierStyleItalic">in vitro</span> that accelerated protocols of 18<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span> for 5<span class="elsevierStyleHsp" style=""></span>min and 36<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span> for 2&#46;5<span class="elsevierStyleHsp" style=""></span>min had similar kill rates &#40;approximately 93&#37;&#41; for <span class="elsevierStyleItalic">Staphylococcus aureus</span> and <span class="elsevierStyleItalic">Pseudomonas aeruginosa compared</span> to the Dresden protocol&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> In the work of Knyazer et al&#46;&#44; PACK-CXL &#40;accelerated protocol&#44; 30<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span> for 3<span class="elsevierStyleHsp" style=""></span>min&#41; was compared together with topical ATBs versus topical ATBs in monotherapy&#44; in patients with BK&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In addition&#44; the treatment costs of both groups were analysed&#46; The authors observed faster re-epithelialisation time&#44; shorter hospitalisations&#44; fewer follow-up visits and a significant reduction in the need for urgent PPQ in the PACK-CXL group&#44; but no significant differences in cost&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The authors consider that this treatment modality could have important implications for healthcare in the context of developing countries and raise it as an interesting avenue for future research&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In this context of underdeveloped regions&#44; which typically have a high prevalence of BK&#44; it is worth considering the potential advantages of PACK-CXL&#44; offering the alternative of a single&#44; short course of therapy&#44; given that it is very difficult to maintain a regimen of frequent visits and proper adherence to treatment in such a context&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">PACK-CXL in bacterial infections</span><p id="par0055" class="elsevierStylePara elsevierViewall">Several studies have shown that PACK-CXL improved BK healing and blocked the progression of corneal thinning and perforation&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Two systematic reviews of PACK-CXL have been published&#44; which together included two RCTs&#46;<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;30</span></a> However&#44; since these systematic reviews were published&#44; other RCTs of PACK-CXL have been conducted&#46; In a recent Cochrane review that focused primarily on the management of BK using papers comparing PACK-CXL in conjunction with standard therapy versus standard therapy in monotherapy&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Two RCTs<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;31</span></a> and one quasi-randomised controlled trial<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> were included&#46; The studies included in the Cochrane review were highly variable with respect to outcome reporting and follow-up times&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Clinical heterogeneity in reported outcomes made it difficult to compare data between RCTs&#46; In addition&#44; there was a wide range of follow-up times&#58; from 14 to 120 days &#40;time to healing&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> The most significant limitation was that the studies provided insufficient information to assess cases of BK&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Two of the 3 studies included keratitis of any etiology&#44; but did not report results based on etiology&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> Ultimately&#44; the authors of this Cochrane review concluded that there was insufficient evidence to support PACK-CXL combination therapy in conjunction with topical ATBs as a safe and effective treatment for BK&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> However&#44; the 5 RCTs currently underway may provide better answers in the next update of this review&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#8211;37</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Papaionnaou et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> evaluated a total of 25 studies in their systematic review&#44; 2 of which are studies previously included in the Cochrane review&#44;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> and concluded that PACK-CXL was more effective in cases of BK &#40;87&#46;2&#37; cured out of 167 eyes&#41;&#44; but again the evidence was low because of the high number of non-randomised studies included&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Makdoumi et al&#46; conducted a prospective study &#40;non-randomised clinical trial&#41; with 16 patients with a clinical diagnosis of BK&#44; in which none of them received ATB treatment prior to inclusion in the study&#44; with the aim of investigating PACK-CXL as a primary therapy for BKs&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> This group observed that all eyes responded to PACK-CXL with improvement of symptoms and signs with respect to reduction of inflammation and healing of the epithelial defect in all cases&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> They observed that 16 patients with BK without prior ATB treatment underwent standard PACK-CXL &#40;Dresden protocol&#59; 3<span class="elsevierStyleHsp" style=""></span>mW&#47;cm<span class="elsevierStyleSup">2</span>&#44; 30<span class="elsevierStyleHsp" style=""></span>min&#41;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a>&#59; 15 patients had complete epithelial closure and all showed signs of improvement and reduced inflammatory response to bacteria&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Two participants required ATB treatment due to poor healing secondary to underlying systemic disease &#40;diabetes with ocular complications&#41; or recurrent epithelial defects&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Ultimately&#44; the authors concluded that PACK-CXL may have potential for the cure of patients with BK&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">The systematic review by Marasini et al&#46; observed that 2 of 5 RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>27&#41;&#44; 2 of 4 non-RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&#41; and 17 of 22 case studies &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>58&#41; evaluated PACK-CXL as a last chance to preserve corneal integrity in recalcitrant infections that did not respond to standard medical treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> However&#44; despite the fact that CXL has shown efficacy in corneal ectasia in halting progression by improving the biomechanical stability of the uninfected cornea&#44; the review by Marasini et al&#46; observed that infected corneas that underwent PACK-CXL perforated or required enucleation in 15&#37; of cases in RCTs&#44; 0&#37; of cases in included non-RCT studies and 12&#37; of patients described in case series&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">A meta-analysis by Ting et al&#46; included 46 studies&#44; of which 4 were RCTs&#44; with 435 patients in total&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Compared to standard ATB monotherapy&#44; adjuvant PACK-CXL in BC resulted in a shorter mean time to complete corneal healing and faster resolution of the infiltrate at both 1 week and 1 month&#44; with no significant difference found in epithelial defect size&#44; best corrected visual acuity and risk of adverse events&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> This review included 4 RCTs with 58 participants in the intervention group &#40;PACK-CXL with standard TMJ therapy&#41; and 57 participants in the control group &#40;standard TMJ therapy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The majority of the studies focused on either KCs&#44; fungal keratitis &#40;FK&#41; or a combination of both&#44; and only one RCT included <span class="elsevierStyleItalic">Acanthamoeba</span> keratitis&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> No RCT examined the usefulness of PACK-CXL in viral keratitis&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> PACK-CXL was superior to ATM therapy in the resolution of infiltrate size at 7 days and at the end of follow-up &#40;14&#8211;30 days&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;29</span></a> PACK-CXL did not reduce the risk of adverse events such as corneal perforation when compared to the ATM therapy alone group&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Three RCTs<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;31&#44;32</span></a> showed a similar or lower risk of adverse effects in the PACK-CXL group&#46; However&#44; Uddaraju et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> observed an opposite trend&#46; Overall&#44; the evidence was of very low quality&#44; with insufficient sample size in the 4 RCTs to achieve sufficient power in terms of efficacy and safety outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Price et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> and Hafezi and Randleman&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> previously estimated that 200&#8211;250 participants are needed to assess the efficacy of PACK-CXL&#44; far short of the number of participants in the RCTs in this meta-analysis&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The other limitation was the inconsistency in measurement and reporting of treatment outcomes among the 4 included RCTs&#44; reporting 8 different outcomes&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In addition&#44; the risk of adverse events was the only outcome that was systematically examined across the 4 RCTs&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Ultimately&#44; this meta-analysis demonstrates that adjuvant PACK-CXL accelerates healing of IK compared to ATM therapy alone&#44; with low quality evidence&#46; Therefore&#44; it shows that more high-quality and adequately powered RCTs are needed to fully determine the therapeutic effect of PACK-CXL&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Prajna et al&#46; noted that no benefit of adjuvant CXL in the primary treatment of BKs could be demonstrated&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> However&#44; they did observe that the CXL group was less likely to have positive cultures at 24<span class="elsevierStyleHsp" style=""></span>h than patients in the group given topical moxifloxacin &#40;0&#46;5&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> Bamdad et al&#46; demonstrated that patients who received CXL and ATB&#44; relative to those in the ATB monotherapy group &#40;topical moxifloxacin 0&#46;5&#37;&#47;h&#41;&#44; had a smaller area of epithelial defect&#44; a smaller area of infiltration and a shorter mean duration of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">In the work of Kasetsuwan et al&#46; they observed that standard combined treatment with PACK-CXL in moderate to severe KC and FK did not provide any benefit over standard treatment alone&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> No significant differences in the size of infiltrates or epithelial defects were observed&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Achiron et al&#46; in their study compared PACK-CXL in combination with standard ATB therapy &#40;26 eyes&#41; to standard ATB therapy alone &#40;21 eyes&#41; in patients with moderate and severe KCB&#46; The authors demonstrated that the combined treatment reduces healing time&#44; improves final visual acuity &#40;VA&#41; and reduces the need for tectonic keratoplasty&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> The authors observed that patients in the first group had more favourable results in terms of number of tectonic grafts &#40;0&#37; in the combined group compared to 33&#46;3&#37; in the standard ATB alone group&#41;&#44; better final uncorrected VA &#40;mean difference&#44; compared to the standard ATB alone group&#44; of 0&#46;57 logMAR&#41; and better final corrected VA &#40;mean difference&#44; compared to the standard ATB alone group&#44; of 0&#46;7 logMAR&#41; and shorter re-epithelialisation time &#40;mean difference of 9&#46;63 days&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">PACK-CXL in <span class="elsevierStyleItalic">Acanthamoeba</span> infections</span><p id="par0095" class="elsevierStylePara elsevierViewall">Four in vitro studies evaluated the impact of UV radiation on <span class="elsevierStyleItalic">Acanthamoeba</span> isolated from corneal ulcers&#44; and reported that the method was ineffective in inhibiting their proliferation&#44;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#8211;45</span></a> while the same treatment&#44; at similar doses&#44; was shown to be effective in some patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46&#8211;48</span></a> However&#44; in the meta-analysis by Ting et al&#46; the evidence on the use of PACK-CXL in <span class="elsevierStyleItalic">Acanthamoeba</span> keratitis and mixed keratitis &#40;MK&#41; was insufficient&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">PACK-CXL in fungal infections</span><p id="par0100" class="elsevierStylePara elsevierViewall">Management of fungal keratitis &#40;FK&#41; is challenging and recurrence of infection can be observed even after keratoplasty &#40;KP&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> Deep corneal vascularisation is a high-risk factor affecting graft survival and optical Pk is often necessary after &#8220;warm&#8221; Pk to obtain satisfactory visual rehabilitation&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> CXL in Boston keratoprosthesis donor corneas results in a lower incidence of corneal dissolution&#44;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> which may be beneficial in preventing deep vascularisation<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> and may alter corneal permeability to drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> Thus&#44; the authors of this study conclude that CXL-treated donor corneas could help reduce the incidence of graft reinfection after keratoplasty in FK&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">The study by Uddaraju et al&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> included severe and refractory FK with involvement of the posterior two-thirds of the cornea and unresponsive to standard antifungal therapy during the previous 2 weeks&#44; so the findings could be confounded by the difference in the initial severity of FK where the PACK-CXL group was much worse than the single ATM therapy group&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Based on these findings&#44; the authors advise against the use of PACK-CXL in severe deep FK&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">The study by Prajna et al&#46; aims to determine if there is any benefit of PACK-CXL in filamentous FK and compares topical natamycin 5&#37; versus topical amphotericin 0&#46;15&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Four groups were randomised&#58; topical natamycin 5&#37;&#44; natamycin 5&#37;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PACK-CXL&#44; amphotericin 0&#46;15&#37; and amphotericin 0&#46;15&#37;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PACK-CXL&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> The results obtained were that patients assigned to the PACK-CXL group&#44; regardless of whether they received natamycin or topical amphotericin&#44; were 1&#46;32 more likely to have culture positivity at 24<span class="elsevierStyleHsp" style=""></span>h&#44; without being statistically significant&#44; and the best corrected VA was 0&#46;22<span class="elsevierStyleHsp" style=""></span>logMAR worse on average at 3 weeks and 0&#46;32<span class="elsevierStyleHsp" style=""></span>logMAR worse at 3 months&#44; among those who received PACK-CXL&#46; No differences were observed in the size of infiltrates and&#47;or scarring&#44; nor in the percentage of adverse events between the groups&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> Ultimately&#44; there appears to be no benefit of adjuvant PACK-CXL in the treatment of filamentous FK&#44; and may even result in a decrease in VA in the PACK-CXL group&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">Cross-Linking Assisted Infection Reduction &#40;CLAIR&#41;</span> RCT observed no benefit of PACK-CXL in the primary management of filamentous FK at 3 months&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> At 12-month follow-up of the CLAIR trial&#44;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> the best corrected VA was 1&#46;8<span class="elsevierStyleHsp" style=""></span>logMAR worse in the PACK-CXL group&#46; No difference in VA was observed between those randomised to topical amphotericin 0&#46;15&#37; versus the topical natamycin 5&#37; group&#44; regardless of whether or not they underwent PACK-CXL&#44; and no difference in ulcer infiltrate and&#47;or scar size was observed between those who received PACK-CXL compared to those who did not&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> There were 10 patients with full-thickness corneal perforation&#44; 4 in the PACK-CXL group and 6 in the topical medication monotherapy group&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> A total of 21 patients ended up in keratoplasty&#44; 11 patients in the PACK-CXL group and 10 patients in the medication only group&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> In summary&#44; at 12 months there was no benefit of PACK-CXL as an adjuvant in the treatment of filamentous FK&#44; in terms of VA&#44; scar size or complications&#44; including perforation and QP&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Bamdad et al&#46; observed in their work that out of 9 patients with FK refractory to conventional treatment&#44; 4 &#40;2 cases caused by <span class="elsevierStyleItalic">Aspergillus</span> and 2 by <span class="elsevierStyleItalic">Fusarium</span>&#41; had a good response to PACK-CXL&#44; with a mean time to complete epithelialisation and a mean time to resolution of stromal infiltration of 14&#46;25<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;38 and 22&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;29 days&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> There were no statistically significant differences between the responder and non-responder groups with respect to mean depth of infiltration and mean ulcer size&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> The authors conclude that PACK-CXL could be added to the therapeutic arsenal of antimicrobial agents for the management of severe and refractory cases of FK&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Recently&#44; a phase 3 RCT has been published&#44; where participants&#44; with BK&#44; FK or MF&#44; were randomised to 2 groups &#40;PACK-CXL vs&#46; ATM therapy&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> In this work&#44; it was observed that the success rate &#40;defined as complete resolution of signs of infection&#41; in the PACK-CXL group &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>18&#41; was 88&#46;9&#37; &#40;16&#47;18 patients&#41;&#44; and 90&#46;5&#37; &#40;19&#47;21 patients&#41; in the ATM therapy group &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>21&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> The authors conclude that PACK-CXL may be an alternative to ATM drugs for the first-line&#44; stand-alone treatment of early to moderate BK&#44; FK or MK&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">PACK-CXL in infectious keratitis after penetrating keratoplasty</span><p id="par0130" class="elsevierStylePara elsevierViewall">The incidence of post-PPK IK varies between 1&#46;76&#37;&#8211;12&#46;1&#37;&#44; with a treatment failure rate in PPKs of 26&#37;&#8211;57&#37; &#40;as opposed to a 10&#37; failure rate in non-PPK IK&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> IKs may account for 5&#46;1&#37;&#8211;32&#46;3&#37; of all indications for PPK&#44; depending on the series&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Due to the long-term use of topical steroids&#44; <span class="elsevierStyleItalic">Staphylococcus</span> and <span class="elsevierStyleItalic">Candida</span> are the main causes of post-PPK IKs&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> In the work of Uzman et al&#46; a higher&#44; but not statistically significant&#44; rate of resolution of BK and QF infiltrates was observed in the PACK-CXL group combined with TMJ therapy &#40;83&#46;3&#37;&#41; compared to the control group&#44; which received TMJ therapy alone &#40;68&#46;2&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> In addition&#44; they observed that the infiltrates did not resolve after PACK-CXL in 2 patients with BK and 1 patient with FK&#44; both of whom had full-thickness corneal stroma involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> The results of Uzman et al&#46; show that the depth of the infiltrate is more important than the type of pathogen&#44; with a 25&#37; resolution rate observed in cases of total corneal involvement with endothelial plaque&#44;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> so that the response to treatment with PACK-CXL seems to be better in early IK&#44; when the infection only affects the superficial layers of the corneal stroma<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a>&#59; this could be explained because the effect of CXL with Dresden protocol is limited to the anterior 300<span class="elsevierStyleHsp" style=""></span>&#956; of the stroma&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> Ultimately&#44; PACK-CXL demonstrated a shorter healing time and a higher proportion of patients with at least 2 lines of visual improvement compared to the group treated with antimicrobial therapy alone&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Infectious keratitis post-CXL</span><p id="par0135" class="elsevierStylePara elsevierViewall">Although CXL has been used for the management of IK&#44; these infections can occur postoperatively with this same technique&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Among the main causes described are the presence of an epithelial defect&#44; the use of contact lenses and&#47;or topical steroids in the immediate postoperative period&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> In the case of IK post-CXL&#44; microbial invasion is likely to occur during the postoperative period rather than during surgery&#44; as this technique not only damages keratocytes but also kills bacteria and fungi&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> In an open-label comparative clinical trial&#44; Tzamalis et al&#46; found that delaying the use of topical steroids until the epithelium healed reduced the likelihood of infection&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In the work of Khoo et al&#46; more than 70&#37; of patients had worn contact lenses within one month prior to infection&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> However&#44; due to the study design it could not be determined whether the use of a contact lens&#44; a topical steroid or their combination leads to an increase in infection&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> The CXL <span class="elsevierStyleItalic">epi-off</span> technique is itself a predisposing risk factor for IK because of the epithelial defect resulting from the technique&#44; which can take 2&#8211;5 days to heal and is an important entry point for microorganisms&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> The organisms described as causing post-CXL IK range from bacteria to herpes simplex virus&#44; fungi and even <span class="elsevierStyleItalic">Acanthamoeba</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> In the work of Khoo et al&#46; 42&#37; of the causative organisms were coagulase negative staphylococci&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> While it is true that CXL may have ATM activity&#44; it may also alter the normal ocular flora&#44; and thus secondarily increase the risk of infection&#44; especially when the corneal epithelium is compromised&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Conclusions</span><p id="par0140" class="elsevierStylePara elsevierViewall">PACK-CXL could serve as a useful therapeutic arsenal to complete healing and reduce the size of the infiltrate in IK<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> but we should note that&#44; to our knowledge&#44; there are no studies &#40;including <span class="elsevierStyleItalic">in vitro</span> studies&#41; that have evaluated the safety of the treatment with respect to its potential genotoxicity&#44; i&#46;e&#46; its ability to induce mutations in cellular genetic information&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Adjustments of CXL treatment parameters&#44; as well as the duration of irradiation and energy used&#44; could help increase the efficacy of PACK-CXL depending on the type of pathogen&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The timing of initiating PACK-CXL could be chosen according to the clinical evolution of the patients&#44; but it is recommended&#44; following current evidence&#44; that PACK-CXL be performed one week after the start of medical treatment in non-responder patients&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The authors of the Cochrane review concluded that there was insufficient evidence to support PACK-CXL combined therapy with topical ATBs as a safe and effective treatment for BK&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> However&#44; Papaionnaou et al&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> and Ting et al&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> concluded that PACK-CXL was more effective in cases of BK &#40;87&#46;2&#37; cured out of 167 eyes&#41;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> and had a shorter mean time to complete corneal healing and faster resolution of the infiltrate&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> although the evidence was low due to the high number of non-randomised studies included&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;30</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The SCUT II study protocol has recently been published&#44; where the authors hope that the results of this work will provide evidence of the efficacy of PACK-CXL and early steroids as adjunctive treatments in KC&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> The authors anticipate that these therapies will improve outcomes such as VA&#44; while reducing the rate of complications such as corneal perforation or the need for therapeutic PK&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Current evidence on the use of PACK-CXL is insufficient for the recommendation of this technique in <span class="elsevierStyleItalic">Acanthamoeba</span> keratitis and MK&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Furthermore&#44; in viral keratitis&#44; PACK-CXL is contraindicated because of the possibility of exacerbating or activating herpes simplex virus infection&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;24&#44;55</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Following the conclusions of the CLAIR study&#44; there appears to be no benefit of adjuvant PACK-CXL in the treatment of filamentous FK either at 3 or 12 months follow-up&#44; and it may even produce a decrease in VA in the PACK-CXL group&#46;<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50&#44;51</span></a> However&#44; Bamdad et al&#46; recommend the use of PACK-CXL in cases of refractory FK to avoid emergency PCI&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">In summary&#44; the current evidence on the effectiveness of PACK-CXL for the management of IK appears to be low&#44; clinically heterogeneous in terms of outcomes<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> and with questionable safety in certain etiologies&#46; Currently&#44; there are 5 ongoing RCTs<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">33&#8211;37</span></a> with 1136 participants&#44; which will hopefully provide more specific and clarifying answers&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">No conflicts of interest were declared by the authors&#46;</p></span></span>"
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          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Methodology"
        ]
        6 => array:3 [
          "identificador" => "sec0015"
          "titulo" => "Corneal cross-linking"
          "secciones" => array:1 [
            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Post-CXL neurotoxicity"
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          "identificador" => "sec0025"
          "titulo" => "Effects of ultraviolet light"
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        8 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Influence of PACK-CXL energy on microbial death rate"
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        9 => array:3 [
          "identificador" => "sec0035"
          "titulo" => "Treatment protocols"
          "secciones" => array:7 [
            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "PACK-CXL standard and variations thereof"
            ]
            1 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "PACK-CXL accelerated"
            ]
            2 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "PACK-CXL in bacterial infections"
            ]
            3 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "PACK-CXL in Acanthamoeba infections"
            ]
            4 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "PACK-CXL in fungal infections"
            ]
            5 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "PACK-CXL in infectious keratitis after penetrating keratoplasty"
            ]
            6 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Infectious keratitis post-CXL"
            ]
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          "identificador" => "sec0075"
          "titulo" => "Conclusions"
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          "titulo" => "Conflicts of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2021-10-30"
    "fechaAceptado" => "2022-02-02"
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          "clase" => "keyword"
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          "palabras" => array:4 [
            0 => "Infectious keratitis"
            1 => "Corneal cross-linking"
            2 => "PACK-CXL"
            3 => "Corneal ulcer"
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          "clase" => "keyword"
          "titulo" => "Palabras clave"
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          "palabras" => array:4 [
            0 => "Queratitis infecciosas"
            1 => "Cross-linking corneal"
            2 => "PACK-CXL"
            3 => "&#218;lcera corneal"
          ]
        ]
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Infectious keratitis &#40;IK&#41; is one of the most common causes of monocular blindness worldwide&#44; especially in developing countries and may account for 5&#46;1&#37;&#8211;32&#46;3&#37; of all indications for penetrating keratoplasty &#40;PK&#41;&#46; However&#44; performing a therapeutic PK on a &#8220;hot eye&#8221; is associated with a higher incidence of IK recurrence and graft rejection&#46; Standard treatment includes antimicrobials &#40;ATM&#41; and&#44; once the causative pathogen has been identified&#44; must be continued with targeted treatment&#44; depending on antibiogram sensitivity&#46; However&#44; appearance of multiresistant strains to ATM is progressively increasing at an alarming rate&#46; Besides that&#44; the diversity of the causative microorganisms &#40;bacteria&#44; fungi&#44; parasites&#44; viruses&#41; may hinder the clinical diagnosis and secondarily the proper treatment from the beginning&#46; It is estimated that only 50&#37; of eyes will have a good visual result if the correct therapy is delayed&#46; All these factors make the identification of alternatives to ATM treatment of paramount importance&#46; Due to the ATM properties of photoactivated chromophore &#40;riboflavin&#44; RB&#41; and ultraviolet &#40;UV&#41; light of wavelength &#40;&#955;&#41; 200&#8211;400 nanometers &#40;nm&#41;&#44; used in multiple medical and non-medical applications for disinfection&#44; photoactivated chromophore for corneal cross-linking &#40;CXL&#41; of IK &#40;PACK-CXL&#41;&#44; as an addition to the therapeutic arsenal for the management of IK has been proposed&#46; It must be differentiated from CXL used for the management of progressive keratoconus &#40;KC&#41;&#46; The objective of this review is to update the available evidence on the efficacy and safety of PACK-CXL in IKs&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Las queratitis infecciosas &#40;QI&#41; es una de las causas m&#225;s comunes de ceguera a nivel mundial&#44; especialmente en pa&#237;ses en v&#237;as de desarrollo y puede llegar a representar del 5&#46;1&#37; al 32&#46;3&#37; de todas las indicaciones de queratoplastia penetrante &#40;QPP&#41;&#46; Sin embargo&#44; realizar una queratoplastia terap&#233;utica en &#8220;caliente&#8221; est&#225; asociado con una mayor incidencia de recurrencia de la QI y rechazo del injerto&#46; El tratamiento est&#225;ndar incluye antimicrobianos &#40;ATM&#41; de amplio espectro y&#44; una vez identificado el pat&#243;geno causante y el antibiograma&#44; continuar con un tratamiento dirigido&#44; seg&#250;n la sensibilidad del germen&#46; La aparici&#243;n de cepas multirresistentes a los ATM est&#225; aumentando progresivamente a un ritmo alarmante en los &#250;ltimos tiempos&#46; Asimismo&#44; la diversidad de los microorganismos causantes &#40;bacterias&#44; hongos&#44; par&#225;sitos&#44; virus&#41; dificultan en ocasiones la realizaci&#243;n de diagn&#243;stico cl&#237;nico correcto&#44; retrasando en inicio de un tratamiento efectivo&#46; Se estima que s&#243;lo un 50&#37; de los ojos tendr&#225; un buen resultado visual si se retrasa la terapia&#46; En definitiva&#44; todos estos factores hacen que sea muy importante la identificaci&#243;n de alternativas al tratamiento ATM&#46; Por las propiedades ATM del crom&#243;foro fotoactivado &#40;riboflavina&#44; RB&#41; y la luz ultravioleta &#40;UV&#41; de longitud de onda &#40;&#955;&#41; 200&#8722;400 nan&#243;metros &#40;nm&#41;&#44; utilizada en m&#250;ltiples aplicaciones m&#233;dicas y no m&#233;dicas para la desinfecci&#243;n&#44; se ha propuesto el crom&#243;foro fotoactivado para el cross-linking &#40;CXL&#41; corneal en el tratamiento de las QI &#40;por sus siglas en ingl&#233;s&#44; PACK-CXL&#41;&#44; como una herramienta adicional en el arsenal terap&#233;utico de las QI&#46; Debe diferenciarse del CXL empleado para el manejo del queratocono &#40;QC&#41; progresivo&#46; El objetivo de esta revisi&#243;n es actualizar la evidencia disponible sobre la eficacia y seguridad de PACK-CXL en las QI&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Hamida Abdelkader SM&#44; Rodr&#237;guez Calvo-de-Mora M&#44; Geg&#250;ndez-Fern&#225;ndez JA&#44; Soler-Ferr&#225;ndez FL&#44; Rocha-de-Lossada C&#46; Revisi&#243;n de la literatura sobre la evidencia disponible actualmente para el manejo de las queratitis infecciosas con PACK-CXL&#46; Arch Soc Esp Oftalmol&#46; 2022&#59;97&#58;464&#8211;472&#46;</p>"
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      "titulo" => "References"
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