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Riboflavin/ultravoilet light-mediated crosslinking for fungal keratitis
  1. Zhiwei Li1,
  2. Vishal Jhanji2,3,
  3. Xiangchen Tao1,
  4. Haiqun Yu1,
  5. Wei Chen4,
  6. Guoying Mu1
  1. 1 Department of Ophthalmology, Provincial Hospital affiliated to Shandong University, Jinan, China
  2. 2 Department of Visual Sciences and Ophthalmology, the Chinese University of Hong Kong, Kowloon, Hong Kong
  3. 3 Centre for Eye Research Australia, University of Melbourne, Australia
  4. 4 Clinical College of Ophthalmology, Tianjin Medical Univeristy, Tianjin, China
  1. Correspondence to Dr Guoying Mu, Department of Ophthalmology, Provincial Hospital affiliated to Shandong University, No. 324, Jing 5 Road, Ji'nan City, Shandong Province, P. R. China, 250021; mgyeyes{at}

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Collagen crosslinking (CXL) has been used to treat cases with bacterial, Acanthamoeba 1 ,2 and fungal keratitis2 with encouraging results. In this study, we present the clinical outcomes in cases with fungal keratitis that received riboflavin/ultravoilet light A (UVA) light-mediated crosslinking.


Patients with microbiologically proven fungal keratitis were included in this study. A written consent was obtained from all the patients. The study protocol was approved by the ethics committee of the Provincial Hospital. Initial treatment was commenced in the form of hourly 5% natamycin eye drops and 0.3% tobramycin eye drops four times a day. A decision was taken to perform CXL after no response to treatment or an exacerbation of infection was observed. Under topical anaesthesia, the epithelium surrounding the infiltrate was removed. Riboflavin (Medio-Cross riboflavin/dextran solution, 0.1%) was administered topically for 30 min at intervals of 2 min. The cornea was illuminated for 30 min using a UV light lamp (UV-X 1000 system, IROC Innocross AG Co, Switzerland; wavelength 365 nm, irradiance 3 mW/cm2, total dose 5.4 J/cm2). Riboflavin administration was continued during UV illumination at the same intervals. Topical 5% natamycin was continued after CXL treatment. Patients were examined on a daily basis thereafter until resolution of the infiltrate. Frequency of eye drops was modified according to the clinical response.


A total of eight patients (four males, four females) with microbiologically proven fungal keratitis were included (table 1). All patients had a history of ocular trauma with vegetative matter or finger nail. An isolated infiltrate was observed in one case, two infiltrates were noted in two cases and more than two infiltrates were noted in five cases. CXL treatment was performed between 5 days and 1 month from the time of initial presentation.

Table 1

Clinical and microbiological characteristics and time to epithelial healing in cases with fungal keratitis after crosslinking treatment

No intraoperative complications were noted in any of the cases. The hypopyon disappeared in all cases between 3 and 11 days after CXL (figures 1 and 2). Healing of corneal epithelium and ulcer was achieved in all cases between 3 and 8 days after CXL treatment (table 1). Post-CXL visual acuity improved in six cases, remained unchanged in one case, and deteriorated in one case. None of the cases required a corneal transplantation.

Figure 1

Clinical photographs of a case with fungal keratitis before collagen crosslinking (CXL) (upper left), on day 3 after CXL (upper right), on day 6 after CXL (lower left), and on day 22 after CXL (lower right). This figure is only reproduced in colour in the online version.

Figure 2

Clinical photographs of a case with fungal keratitis before collagen crosslinking (CXL) (left), on day 6 after CXL (middle), and on day 12 after CXL (right). This figure is only reproduced in colour in the online version.


Recent reports have highlighted the potential use of CXL treatment for management of cases with infectious keratitis.1–3 In our study, resolution of infection and epithelial healing were achieved in all the cases after CXL. Furthermore, none of the cases required corneal transplantation.

The effect of UVA/riboflavin combination in pathogen elimination has been described in transfusion medicine.4 However, the exact mechanism of bactericidal effect of the UVA/riboflavin combination is not yet fully known.5 A shift in the response to CXL-induced changes in the mechanical properties of cornea may enhance the corneal resistance against microbial degradation and corneal melting. CXL also induces apoptosis6 which could contribute to the reduction of the inflammatory response during corneal infection.

Fungal corneal infections are usually more deep-seated compared with bacterial infections, whereas the effect of CXL may be limited to the anterior layers of the cornea. In our study, a majority of the ulcers were not very extensive or advanced. Furthermore, it is possible that epithelial debridement during CXL as well as continuous use of intensive antifungal therapy before and after CXL treatment may have contributed to resolution of infection in our cases. Another limitation of our study is that instead of the recommended 2–4 weeks of treatment, all the cases received antifungal treatment in the form of topical natamycin 5% eye drops for a variable time period before CXL.

In conclusion, this case series suggests that UVA/riboflavin crosslinking is a viable option for management of fungal keratitis, thereby precluding corneal transplantation surgery in these cases. Further randomised clinical trials would be required to evaluate whether CXL can be used as the first line of management for cases with fungal corneal infection.


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  • Contributors Concept and design: ZL and VJ. Analysis and interpretation: ZL and VJ. Writing the article: ZL, VJ, XT, HY, WC and GM. Critical revision of the article: ZL and VJ. Final approval of the article: ZL, VJ, XT, HY, WC and GM. Data collection: ZL. Provision of materials, patients or resources: ZL, XT, HY, WC and GM. Statistical expertise: ZL and VJ. Obtaining funding: ZL and GM. Literature search: ZL and VJ.

  • Funding This study was supported by the Natural Science Foundation of Shandong Province (ZR2012HM008).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The ethic committee of the Provincial Hospital affiliated to Shandong University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • ▸ Additional material is published online only. To view please visit the journal online (

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