Photoactivated chromophore-corneal cross-linking accelerates corneal healing in fungal keratitis: an updated meta-analysis
Systematic Reviews volume 12, Article number: 208 (2023)
To determine the effectiveness and safety of photoactivated chromophore-corneal cross-linking (PACK-CXL) adjuvant in infectious keratitis by April 5, 2022.
We searched randomized controlled trials (RCTs) comparing standard antibiotic treatment (SAT) plus PACK-CXL to SAT in infectious keratitis in Embase, MEDLINE with PubMed, Web of Science, and Cochrane Library. We independently screened and extracted data using predesigned tables. Cochrane’s risk-of-bias tool was utilized to examine the quality of RCTs. A random-effects model was employed to determine the overall effect size of the meta-analyses. Grading of Recommendations, and Assessment, Development and Evaluations (GRADE) was also performed to examine the quality of evidence.
Seven eligible RCTs with 283 patients were acquired. Adjuvant PACK-CXL reduced the time needed to perform corneal healing in fungal keratitis (− 1.33 months; 95% CI, − 1.83 to − 0.42, I2 = 0%, P < 0.05) as compared to SAT alone. The risks of adverse events were not significantly different both in fungal and bacterial keratitis. Due to the substantial heterogeneity among studies, such as population, the type and severity of infectious keratitis, drug regimens of SAT, PACK-CXL protocol, and the judgment of subjective outcomes, the evidence grade was low.
Adjuvant PACK-CXL accelerates fungal keratitis healing as compared to SAT alone. But more rigorous RCTs are required to determine the clinical effectiveness and safety.
Infectious keratitis is the fifth leading cause of blindness overall causing 3.5% (36 million) of all blind individuals up to 2015 . The incidence of infectious keratitis differs worldwide . It has been reported at 2.5 to 40.3 cases per 100,000 population/year in developed countries while as high as 113 to 799 cases per 100,000 population/year in developing countries [1,2,3]. Infectious keratitis can be caused by a wide variety of pathogens, including bacteria, fungi, viruses, and parasites such as acanthamoeba . Because of the high morbidity and considerable societal burden, the prevention and treatment of infectious keratitis are crucial [3, 4]. Both antimicrobial treatment and surgical intervention, such as topical antimicrobial drug administration, amniotic membrane transplantation, and therapeutic penetrating keratoplasty, have been performed . One novel intervention is the application of photoactivated chromophore for keratitis-corneal cross-linking (PACK-CXL) .
Ting et al. conducted a meta-analysis in 2019 that included forty-six studies (four RCTs) assessing PACK-CXL for infectious keratitis. When compared to SAT alone, PACK-CXL was characterized by a shortened mean duration for corneal healing and a quicker clearance of corneal infiltration . Papaioannou et al. conducted a similar meta-analysis in 2016 which included twenty-five studies (including two RCTs). PACK-CXL seems promising in handling infectious keratitis excluding herpetic keratitis, with increased expectations for bacterial and acanthamoeba cases comparing with fungal keratitis . Davis et al. conducted a meta-analysis in 2020 that included three trials (two RCTs and one quasi-RCT), which reached the opposite conclusion. It is very uncertain whether PACK-CXL with SAT is more effective than SAT alone for re-epithelialization and complete healing in bacterial keratitis . Not only RCTs but also case reports, quasi-RCTs, and case series were eligible in these meta-analyses, so high heterogeneity across studies was inevitable. Thus, the application of PACK-CXL in infectious keratitis remains controversial . Another four newly published RCTs, including 208 patients focused on the same topic, have been identified [11,12,13,14]. Therefore, a comprehensive review and meta-analysis including only RCTs were performed to determine the effectiveness and safety of an adjuvant PACK-CXL in infectious keratitis.
This study was conducted in line with the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA 2020; Supplementary materials) [15, 16].
Relevant articles, limited to human and RCTs in Embase, MEDLINE with PubMed, Web of Science, and Cochrane Library, were searched and published up to April 5, 2022, by two authors (S. Y. Liu and S. F. Fang). The search strategy contained three components: clinical condition (“keratitis,” “corneal ulcer”), intervention (“cross-linking reagents,” “riboflavin,” “anti-infective agents”, “ultraviolet therapy,” “photosensitizing agents,” “ultraviolet rays,” “collagen”), and study type (randomized clinical trial). Detailed search strategies are provided in the Supplementary materials. Further, the reference lists in the eligible RCTs were examined manually in case that there were other eligible studies. This procedure was repeated until no more studies were discovered.
Participants: Patients suffering from infectious keratitis with confirmed diagnosis, encompassing bacterial and fungal cases
Intervention: Adjuvant PACK-CXL
Comparison: Standard antimicrobial treatment (SAT) alone
Primary outcome: The duration of corneal healing performed, characterized as thorough corneal re-epithelialized and corneal infiltration and/or hypopyon eradication
Secondary outcome: The size of corneal epithelial defect at 1 week, the size of corneal infiltrate at 1 week, the depth of corneal infiltrate at final follow-up, visual acuity (mean logarithm of the minimum angle of resolution) at final follow-up, and adverse events: worsening infectious keratitis and/or corneal melt requiring tectonic or therapeutic keratoplasty or evisceration at final follow-up (1 to 6 months).
Study type: Randomized controlled trials (RCTs)
Individuals who received extra interventions except antimicrobial treatment which might accelerate corneal healing were excluded.
Based on predefined criteria, two authors (S. Y. Liu and S. F. Fang) independently selected the title and abstract of the 1256 studies identified by the search. Following that, we downloaded the full texts of these articles and conducted a review. Another author (L. J. Zhang) examined the data. Discussions were also performed if there was a divergence.
Two authors (S. Y. Liu and S. F. Fang) independently extracted data in the included RCTs: first author, publication year, sample size, patient characteristics, the protocol of adjuvant PACK-CXL, drug regimen, and other outcomes data. Another author (L. J. Zhang) examined the data. Discussions were also performed if there was a divergence.
Cochrane Collaboration’ s tool was utilized to identify the risk of bias . Trials were scored as high, low, or unclear based on the following items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The study with high risk for ≧ 1 item was regarded as high risk, and the study with low risk for all items was regarded as low risk. Otherwise, the study was regarded as unclear risk .
Data synthesis and analysis
Risk ratio (RR) with its 95% confidence interval (CI) for dichotomous outcome and mean difference (MD) with its 95% CI for continuous outcome were conducted. A random-effects model was utilized due to the clinical heterogeneity. Two-sided P < 0.05 was regarded as statistically significant. Statistical analyses were performed in RevMan 5.3 software.
Certainty of evidence
Certainty of evidence was examined using Grading of Recommendations, and Assessment, Development and Evaluations (GRADE) [19, 20], and summary tables were obtained through GRADE profiler online (https://gradepro.org/).
A total of 1256 studies were screened, in which 278 duplicate publications (22%) and 958 irrelevant studies (76%) were excluded after the initial screening. Full text of the twenty (2%) studies were acquired for further evaluation. Thirteen studies were excluded: two conference abstracts [21, 22], one editorial , one protocol , four studies without RCT design [25,26,27,28], two letters to the editor [29, 30], one study with duplicate data , one secondary analysis , one compares PACK-CXL only with SAT only . Finally, seven RCTs were included [11,12,13,14, 34,35,36], and the procedure is shown in Fig. 1.
The characteristics of these RCTs were shown in Table 1. The publication year ranged from 2015 to 2022, and the sample size ranged from 13 to 111 (together, 283). Eighty patients were diagnosised as bacterial keratitis, and 203 patients were diagnosised as fungal keratitis. One-hundred thirty-nine patients received adjuvant PACK-CXL and SAT, while 144 patients received SAT only. All the trials recorded adverse events [11,12,13,14, 34,35,36], three trials reported the duration of corneal healing performed [11, 13, 34], two trials reported the size of corneal epithelial defect at 1 week [34, 36], three trials reported the size of corneal infiltrate at 1 week [11, 34, 36], only one trial reported the depth of corneal infiltrate at final follow-up , and six trials reported visual acuity at final follow-up [11,12,13,14, 35, 36].
Risk of bias
Risk-of-bias assessment for the seven trials was presented in Fig. 2. All the trials were classified as with a high risk of bias.
The duration of corneal healing performed
Fifty-two patients with fungal keratitis in two trials were included (27 patients with adjuvant PACK-CXL) [11, 13]. Thirty-two patients with bacterial keratitis in one trial were included (16 patients with adjuvant PACK-CXL) . Adjuvant PACK-CXL significantly reduced the time needed to perform corneal healing in fungal keratitis (MD = − 1.13, 95% CI, − 1.83 to − 0.42, P < 0.05), with low heterogeneity among the two trials (I2 = 0%, P = 0.33) (Fig. 3).
The size of corneal epithelial defect (mm2) at 1 week
Eighteen patients with fungal keratitis in one trial were included (eight patients with adjuvant PACK-CXL) . Forty-four patients with bacterial keratitis in two trials were included (23 patients with adjuvant PACK-CXL) [34, 36]. All these trials found that adjuvant PACK-CXL could not reduced the size of corneal epithelial defect at 1 week in fungal and bacterial keratitis. However, Kasetsuwan et al. presented this outcome with “median, quartile,” and we failed to perform a meta-analysis.
The size of corneal infiltrate (mm2) at 1 week
Fifty-one patients with fungal keratitis in two trials were included (29 patients with adjuvant PACK-CXL) [11, 36]. Fifty-four patients with bacterial keratitis in two trials were included (23 patients with adjuvant PACK-CXL) [34, 36]. For fungal keratitis, all these trials found that adjuvant PACK-CXL could not reduced the size of corneal infiltrate at 1 week. For bacterial keratitis, it was controversial. Bamdad et al. found that adjuvant PACK-CXL could reduced the size of corneal infiltrate at 1 week, while Kasetsuwan et al. found that it could not. However, Kasetsuwan et al. presented this outcome with “median, quartile,” and we failed to perform a meta-analysis.
The depth of corneal infiltrate (μm) at final follow-up
Only one trial was included; the ulcer depth did not reduce with the administration of PACK-CXL (P > 0.05) . Therefore, analysis was not carried out.
Visual acuity (mean logarithm of the minimum angle of resolution) at final follow-up
Two-hundred three patients with fungal keratitis in five trials were included (99 patients with adjuvant PACK-CXL) [11,12,13, 35, 36]. Forty-eight patients with bacterial keratitis in two trials were included (24 patients with adjuvant PACK-CXL) [14, 36]. All these trials found that adjuvant PACK-CXL could not improve visual acuity, even might result in decreased visual acuity. However, some RCTs presented this outcome with “median, quartile,” and we failed to perform a meta-analysis.
One-hundred eighty-five patients with fungal keratitis in four trials were included (91 patients with adjuvant PACK-CXL) [11,12,13, 35]. Sixty-eight patients with bacterial keratitis in one trial were included (33 patients with adjuvant PACK-CXL) [14, 34]. Adjuvant PACK-CXL could not reduce adverse events in both fungal and bacterial keratitis (RR = 0.78, 95% CI, 0.38 to 1.60, P = 0.49; RR = 0.36, 95% CI, 0.08 to 1.71, P = 0.20, respectively) (Figs. 4 and 5).
Quality of evidence
GRADE evidence is presented in Table 2. In terms of the duration of corneal healing performed, and adverse events risk, the certainty of evidence was low.
We reviewed the relevant studies that compared the effectiveness and safety of adjuvant PACK-CXL versus SAT alone in infectious keratitis comprehensively and systematically. Adjuvant PACK-CXL reduced the time needed to perform corneal healing as compared to SAT alone in fungal keratitis. The risks of adverse events were not significantly different in both fungal and bacterial keratitis.
Compared with published literature
For the primary outcome, the duration of corneal healing performed, two studies on this subject have been published but reached the opposite conclusion. Davis et al. revealed that it was very uncertain whether adjuvant PACK-CXL was more effective than SAT alone for reepithelialization and complete healing . While Ting et al. found that when compared to SAT alone, adjuvant PACK-CXL resulted in shorter mean time to complete corneal healing . Different types of infectious keratitis may be the underlying reason for this divergence. Therefore, we conducted a subgroup analysis based on infection type and revealed that adjuvant PACK-CXL could reduce the time needed to perform corneal healing as compared to SAT alone in fungal keratitis. For the risks of adverse effects, we also conducted subgroup analyses based on infection type. In accordance with the previous study, adjuvant PACK-CXL could not reduce the risks of adverse effects as compared to SAT alone in both bacterial and fungal keratitis .
Certain differences should be highlighted. Firstly, previous studies included case reports, quasi-RCTs, and case series. To achieve reliable estimates, we set strict inclusion criteria. Only the RCTs clarified clearly the enrollment of patients with adjuvant PACK-CXL were included. We further included another four newly published RCTs with 208 patients published in 2019–2021 in this meta-analysis, which promoted statistical power [11,12,13,14]. Secondly, we conducted subgroup analyses based on infection type. Thirdly, due to clinical heterogeneity, a random-effects model was chosen to guarantee a more conservative estimation. Lastly, the GRADE method was employed to evaluate the certainty of evidence in order to assist clinical practice. Therefore, the present study was the most updated and thorough, reinforcing prior results.
Clinical practice implication
In recent years, the antimicrobial effect of PACK-CXL has been investigated in infectious keratitis [37, 38]. However, the administration of PACK-CXL in infectious keratitis was still controversial [39, 40].
We analyzed the suspected reasons, and possible explanations are as follows. Firstly, the clinical outcomes and the risk of adverse events may be related to the severity of infectious keratitis. Uddaraju et al. enrolled patients with culture-positive deep stromal fungal keratitis who had not responded to appropriate treatment for 2 weeks . The poor response could be explained that fungal infections penetrated deeper, and the intensity of UV-A light would not be sufficient to treat. Early and superficial fungal keratitis responded well to PACK-CXL [27, 41]. While in advanced and deep stromal fungal keratitis, it was hard to determine whether the infection reacted to PACK-CXL alone . Secondly, drug regimens of SAT were not uniform in the seven eligible trials. Thirdly, although most of the included studies used the standard Dresden protocol that UV-A radiation exposure of 3 mW/cm2 for 30 min, the lengths of wave were different, 365 nm or 370 nm. The efficacy of PACK-CXL followed the Bunsen-Roscoe law of reciprocity, and higher fluence or irradiance substantially increased the killing rates [33, 43], while some study suggested that accelerated PACK-CXL provided an antimicrobial effect similar to the low-intensity, slow setting . Therefore, safety limits for clinical application are required in further studies. Lastly, different causative microorganisms were included in this study. Alio et al. revealed that PACK-CXL decreased corneal melting with the following order from most to least: gram-negative bacteria, gram-positive bacteria, acanthamoeba, and fungus . It was worth noting that PACK-CXL presented a weaker killing effect in acanthamoeba, and even be a risk of activating the latent virus, so PACK-CXL should be applied carefully, in patients with acanthamoeba or viral keratitis [46, 47]. In short, ophthalmologists should pay more attention to the type and severity of infectious keratitis, drug regimens of SAT, and PACK-CXL protocol in clinical practice.
Strengths and limitations
The strength of the present study was that only RCTs were included to reduce heterogeneity. And GRADE method was applied to examine the certainty of evidence. There were some limitations in the present study which may affect the interpretation. Firstly, all the included trials presented detailed data; however, different trials focused on different outcomes or documented the same outcome at different follow-up time. So, it was hard to synthesize the data and perform meta-analysis. Secondly, since only seven trials were included, it was difficult to deny the heterogeneity between the included studies. The heterogeneity may come from the following: population, the type and severity of infectious keratitis, drug regimens of SAT, PACK-CXL protocol, and the judgment of subjective outcomes. All these factors may lead to the lack of precise proof to recommend PACK-CXL as a potential approach in infectious keratitis. For further RCTs trials, we suggested that the type and severity of infectious keratitis, drug regimens of SAT, and PACK-CXL protocol should be in the consistency, making the outcomes be more comparable. Meanwhile, the judgment of subjective outcomes should be performed by at least two ophthalmologists, making the data more precise. Therefore, more RCTs comparing cases with similar baseline are needed.
The present study suggests that adjuvant PACK-CXL accelerates corneal healing in fungal keratitis compared with SAT alone. Ophthalmologists should pay more attention to the type and severity of infectious keratitis, drug regimens of SAT, and PACK-CXL protocol in clinical practice. And more rigorous trials are needed in the future.
Availability of data and materials
The data sets in the study are presented in the article or supplementary material, and further information can be directed to the authors.
Maria C-A, Pauline K. Watson Stephanie L, Infectious keratitis: a review. Clin Exp Ophthalmol. 2022;50:543–62.
Ting DSJ, Ho CS, Deshmukh R, et al. Infectious keratitis: an update on epidemiology, causative microorganisms, risk factors, and antimicrobial resistance. Eye (Lond). 2021;35:1084–101.
Fiona S. The epidemiology of infectious keratitis. Ocul Surf. 2023;28:351–63.
Collier Sarah A, Gronostaj Michael P, MacGurn Amanda K, et al. Estimated burden of keratitis–United States, 2010. MMWR Morb Mortal Wkly Rep. 2014;63:1027–30.
Hoffman JJ, Burton MJ, Leck A. Mycotic keratitis- a global threat from the filamentous fungi. J Fungi. 2021;7:273.
Hafezi F, Randleman JB. PACK-CXL: defining CXL for infectious keratitis. J Refract Surg. 2014;30:438–9.
Ting DSJ, Henein C, Said DG, Dua HS. Photoactivated chromophore for infectious keratitis–corneal cross-linking (PACK-CXL): a systematic review and meta-analysis. Ocul Surf. 2019;17:624–34.
Papaioannou L, Miligkos M, Papathanassiou M. Corneal collagen cross-linking for infectious keratitis: a systematic review and meta-analysis. Cornea. 2016;35:62–71.
Davis S, Bovelle R, Han G, Kwagyan J. Corneal collagen cross-linking for bacterial infectious keratitis. The Cochrane Database of Systematic Reviews. 2020;6:CD013001–CD013001.
Raj N, Vanathi M, Ahmed NH. et al. Recent perspectives in the management of fungal keratitis. J Fungi Basel. 2021;7:undefined.
Wei A, Wang K, Wang Y, Gong L, Xu J, Shao T. Evaluation of corneal cross-linking as adjuvant therapy for the management of fungal keratitis. Graefes Arch Clin Exp Ophthalmol. 2019;257:1443–52.
Prajna NV, Radhakrishnan N, Lalitha P, Austin A, Ray KJ, Keenan JD, et al. Cross-linking–assisted infection reduction: a randomized clinical trial evaluating the effect of adjuvant cross-linking on outcomes in fungal keratitis. Ophthalmology. 2020;127:159–66.
Jeyalatha Mani V, Parthasarathy D, Padmanabhan P, Narayanan N, Lakshmipathy M, Pachayappan SK, et al. Therapeutic effect of corneal crosslinking on fungal keratitis: efficacy of corneal collagen crosslinking as an adjuvant therapy for fungal keratitis in a tertiary eye hospital in South India. Ocul Immunol Inflamm. 2021;29:1648–55.
Prajna NV, Radhakrishnan N, Lalitha P, et al. Cross-linking assisted infection reduction (CLAIR): a randomized clinical trial evaluating the effect of adjuvant cross-linking on bacterial keratitis. Cornea. 2021;40:837–41.
Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev. 2019;10:ED000142.
Moher D, Liberati A, Tetzlaff J, Altman DG, Group* P. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. Ann Intern Med. 2009;151:264–9.
Higgins J, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
Gu W-J, Wei C-Y, Yin R-X. Lack of efficacy of probiotics in preventing ventilator-associated pneumonia. Chest. 2012;142:859–68.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–6.
Rose-Nussbaumer J, Austin A, Porco TC, Prajna V, Naveen R. Cross-linking assisted infection reduction: a randomized clinical trial (CLAIR). Invest Ophthalmol Visual Sci. 2019;60:2222.
Aguilar LP, Jimenez-Corona A, Sanchez-Huerta V, Lichtinger A, Hernandez-Quintela E, Graue-Hernandez EO. The efficacy and safety of accelerated collagen crosslinking (CXL) for infectious keratitis: a randomized clinical trial. Invest Ophthalmol Visual Sci. 2018;59:1570.
Dua HS, Said DG. Corneal collagen cross linking: crossing out the microbes. J EuCornea. 2019;3:22–3.
Copeland RA Jr, Davis SA, Lee YJ, Kwagyan J, Bovelle R. Corneal collagen cross-linking for infectious keratitis. Cochrane Database Syst Rev. 2018;2018:CD03001.
Makdoumi K, Mortensen J, Sorkhabi O, Malmvall B-E, Crafoord S. UVA-riboflavin photochemical therapy of bacterial keratitis: a pilot study. Graefes Arch Clin Exp Ophthalmol. 2012;250:95–102.
Price MO, Tenkman LR, Schrier A, Fairchild KM, Trokel SL, Price FW Jr. Photoactivated riboflavin treatment of infectious keratitis using collagen cross-linking technology. J Refract Surg. 2012;28:706–13.
Erdem E, Harbiyeli II, Boral H, Ilkit M, Yagmur M, Ersoz R. Corneal collagen cross-linking for the management of mycotic keratitis. Mycopathologia. 2018;183:521–7.
Said DG, Elalfy MS, Gatzioufas Z, El-Zakzouk ES, Hassan MA, Saif MY, et al. Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting. Ophthalmology. 2014;121:1377–82.
Olivier R, Johnny M, Farhad H, et al. Corneal cross-linking as an adjuvant therapy in the management of recalcitrant deep stromal fungal keratitis: a randomized trial. Am J Ophthalmol. 2015;160:616–7.
Farhad H, Sabine K. Photoactivated chromophore for moderate to severe infectious keratitis as an adjunct therapy: a randomized controlled trial. Am J Ophthalmol. 2016;168:293–4.
Prajna NV, Radhakrishnan N, Lalitha P, Austin A, Liu Z, Keenan JD, et al. Cross-linking assisted infection reduction: one-year follow-up of a randomized clinical trial evaluating cross-linking for fungal keratitis. Ophthalmology. 2021;128:950–2.
Prajna NV, Radhakrishnan N, Lalitha P, Liu Z, Keenan JD, Arnold BF, Rose-Nussbaumer J. Mediators of the effect of corneal cross-linking on visual acuity for fungal ulcers: a prespecified secondary analysis from the cross-linking-assisted infection reduction trial. Cornea. 2022;41(10):1217–21.
Hafezi F, Hosny M, Shetty R, et al. PACK-CXL vs antimicrobial therapy for bacterial, fungal, and mixed infectious keratitis: a prospective randomized phase 3 trial. Eye Vis (Lond). 2022;9:2.
Bamdad S, Malekhosseini H, Khosravi A. Ultraviolet A/riboflavin collagen cross-linking for treatment of moderate bacterial corneal ulcers. Cornea. 2015;34:402–6.
Uddaraju M, Mascarenhas J, Das MR, Radhakrishnan N, Keenan JD, Prajna L, et al. Corneal cross-linking as an adjuvant therapy in the management of recalcitrant deep stromal fungal keratitis: a randomized trial. Am J Ophthalmol. 2015;160(131–134):e135.
Kasetsuwan N, Reinprayoon U, Satitpitakul V. Photoactivated chromophore for moderate to severe infectious keratitis as an adjunct therapy: a randomized controlled trial. Am J Ophthalmol. 2016;165:94–9.
Vazirani J, Vaddavalli PK. Cross-linking for microbial keratitis. Indian J Ophthalmol. 2013;61:441.
Vajpayee RB, Shafi SN, Maharana PK, Sharma N, Jhanji V. Evaluation of corneal collagen cross-linking as an additional therapy in mycotic keratitis. Clin Experiment Ophthalmol. 2015;43:103–7.
Bonzano C, Di Zazzo A, Barabino S, Coco G, Traverso CE. Collagen cross-linking in the management of microbial keratitis. Ocul Immunol Inflamm. 2019;27:507–12.
Bamdad S, Khalili MR, Khosravi A, Attarzade A, Movahedan H, Nejabat M. Corneal cross-linking as an adjunct for the management of refractory fungal keratitis. Middle East Afr J Ophthalmol. 2020;27:204.
Basaiawmoit P, Selvin SST, Korah S. PACK-CXL in reducing the time to heal in suppurative corneal ulcers: observations of a pilot study from South India. Cornea. 2018;37:1376–80.
Thakur A, Gupta A, Handa S. Application of photoactivated chromophore for infectious keratitis-corneal collagen crosslinking for fungal phaco-tunnel infection. Indian J Ophthalmol. 2019;67:1700.
Richoz O, Kling S, Hoogewoud F, Hammer A, Tabibian D, Francois P, et al. Antibacterial efficacy of accelerated photoactivated chromophore for keratitis–corneal collagen cross-linking (PACK-CXL). J Refract Surg. 2014;30:850–4.
Kling S, Hufschmid FS, Torres-Netto EA, Randleman JB, Willcox M, Zbinden R, et al. High fluence increases the antibacterial efficacy of PACK cross-linking. Cornea. 2020;39:1020–6.
Alio JL, Abbouda A, Valle DD, Del Castillo JMB, Fernandez JAG. Corneal cross linking and infectious keratitis: a systematic review with a meta-analysis of reported cases. J Ophthal Inflamm Infect. 2013;3:1–7.
Knyazer B, Krakauer Y, Baumfeld Y, Lifshitz T, Kling S, Hafezi F. Accelerated corneal cross-linking with photoactivated chromophore for moderate therapy-resistant infectious keratitis. Cornea. 2018;37:528–31.
Atalay HT, Dogruman-Al F, Sarzhanov F, Özmen MC, Tefon AB, Arıbaş YK, et al. Effect of riboflavin/rose Bengal-mediated PACK-CXL on acanthamoeba trophozoites and cysts in vitro. Curr Eye Res. 2018;43:1322–5.
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Liu, S., Fang, S. & Zhang, L. Photoactivated chromophore-corneal cross-linking accelerates corneal healing in fungal keratitis: an updated meta-analysis. Syst Rev 12, 208 (2023). https://doi.org/10.1186/s13643-023-02380-5