Top

Graefe's Archive for Clinical and Experimental Ophthalmology

Published in:

01-07-2019 | Cornea

Evaluation of corneal cross-linking as adjuvant therapy for the management of fungal keratitis

Authors: Anji Wei, Kaidi Wang, Yan Wang, Lan Gong, Jianjiang Xu, Tingting Shao

Published in: Graefe's Archive for Clinical and Experimental Ophthalmology | Issue 7/2019

Abstract

Purpose

To evaluate the efficacy of corneal cross-linking (CXL) as adjuvant therapy for the treatment of fungal ulcerative keratitis.

Methods

Forty-one patients with fungal ulcerative keratitis were recruited and assigned into two randomized controlled groups. These groups were treated with CXL combined with antifungal medications (CXL-M) or antifungal medications alone (M). The ulcers were assessed by slit-lamp biomicroscopy, slit-lamp images, in vivo confocal microscopy (IVCM), and anterior segment optical coherence tomography (AS-OCT). The patients were followed up before surgery/first visit (FV), 1 day after surgery, 1 and 2 weeks, and 1, 2, 3, 4, 5, and 6 months after surgery/FV.

Results

In the cured patients, the area of corneal ulcers, the duration of ulcer healing, the time to non-observed fungal hyphae by IVCM, the number of antifungal medications, the frequency of administered medications, and the maximum ulcer depth decreased significantly after CXL (all P < 0.05) compared with the M group. There were no significant differences in either corneal thickness or epithelial thickness of ulcers after healing between 5 and 6 months after surgery in the CXL-M group, while these were increased significantly at 6 months compared with 5 months after FV in the M group (both P < 0.05).

Conclusions

In our study, CXL accelerated healing of the fungal ulcers, shortened the treatment duration, and minimized the need for medications and surgery. It appears that CXL is an effective procedure and adjuvant therapy for managing fungal keratitis.

Kernt M, Kampik A (2009) Intracameral voriconazole: in vitro safety for human ocular cells. Toxicology 258:84–93. https://doi.org/10.1016/j.tox.2009.01.008 CrossRefPubMed

Wu J, Zhang WS, Zhao J, Zhou HY (2016) Review of clinical and basic approaches of fungal keratitis. Int J Ophthalmol 9:1676–1683. https://doi.org/10.18240/ijo.2016.11.23 CrossRefPubMedPubMedCentral

Prajna NV, Srinivasan M, Lalitha P, Krishnan T, Rajaraman R, Ravindran M, Mascarenhas J, Oldenburg CE, Ray KJ, McLeod SD, Acharya NR, Lietman TM (2013) Differences in clinical outcomes in keratitis due to fungus and bacteria. JAMA Ophthalmol 131:1088–1089. https://doi.org/10.1001/jamaophthalmol.2013.1612 CrossRefPubMed

Fini ME, Cook JR, Mohan R (1998) Proteolytic mechanisms in corneal ulceration and repair. Arch Dermatol Res 290 Suppl:S12–S23CrossRefPubMed

Anwar HM, El-Danasoury AM, Hashem AN (2011) Corneal collagen crosslinking in the treatment of infectious keratitis. Clin Ophthalmol 5:1277–1280. https://doi.org/10.2147/OPTH.S24532 CrossRefPubMedPubMedCentral

Martins SA, Combs JC, Noguera G, Camacho W, Wittmann P, Walther R, Cano M, Dick J, Behrens A (2008) Antimicrobial efficacy of riboflavin/UVA combination (365 nm) in vitro for bacterial and fungal isolates: a potential new treatment for infectious keratitis. Invest Ophthalmol Vis Sci 49:3402–3408. https://doi.org/10.1167/iovs.07-1592 CrossRefPubMed

Kimakura M, Usui T, Yokoo S, Nakagawa S, Yamagami S, Amano S (2014) Toxicity of topical antifungal agents to stratified human cultivated corneal epithelial sheets. J Ocul Pharmacol Ther 30:810–814. https://doi.org/10.1089/jop.2014.0044 CrossRefPubMedPubMedCentral

Baier J, Maisch T, Maier M, Engel E, Landthaler M, Baumler W (2006) Singlet oxygen generation by UVA light exposure of endogenous photosensitizers. Biophys J 91:1452–1459. https://doi.org/10.1529/biophysj.106.082388 CrossRefPubMedPubMedCentral

Garg P, Das S, Roy A (2017) Collagen cross-linking for microbial keratitis. Middle East Afr J Ophthalmol 24:18–23. https://doi.org/10.4103/meajo.MEAJO_305_16 CrossRefPubMedPubMedCentral

10.

Kymionis GD, Mikropoulos DG, Portaliou DM, Voudouragkaki IC, Kozobolis VP, Konstas AG (2013) An overview of corneal collagen cross-linking (CXL). Adv Ther 30:858–869. https://doi.org/10.1007/s12325-013-0065-9 CrossRefPubMed

11.

Alhayek A, Lu PR (2015) Corneal collagen crosslinking in keratoconus and other eye disease. Int J Ophthalmol 8:407–418. https://doi.org/10.3980/j.issn.2222-3959.2015.02.35 CrossRefPubMedPubMedCentral

12.

O'Brart DP, Patel P, Lascaratos G, Wagh VK, Tam C, Lee J, O'Brart NA (2015) Corneal cross-linking to halt the progression of keratoconus and corneal ectasia: seven-year follow-up. Am J Ophthalmol 160:1154–1163. https://doi.org/10.1016/j.ajo.2015.08.023 CrossRefPubMed

13.

Li G, Fan ZJ, Peng XJ (2012) Corneal collagen crosslinking for corneal ectasia of post-LASIK: one-year results. Int J Ophthalmol 5:190–195. https://doi.org/10.3980/j.issn.2222-3959.2012.02.15 CrossRefPubMedPubMedCentral

14.

Sharma N, Roy S, Maharana PK, Sehra SV, Sinha R, Tandon R, Titiyal JS, Vajpayee RB (2014) Outcomes of corneal collagen crosslinking in pseudophakic bullous keratopathy. Cornea 33:243–246. https://doi.org/10.1097/ICO.0000000000000004 CrossRefPubMed

15.

Alshehri JM, Caballero-Lima D, Hillarby MC, Shawcross SG, Brahma A, Carley F, Read ND, Radhakrishnan H (2016) Evaluation of corneal cross-linking for treatment of fungal keratitis: using confocal laser scanning microscopy on an ex vivo human corneal model. Invest Ophthalmol Vis Sci 57:6367–6373. https://doi.org/10.1167/iovs.16-20110 CrossRefPubMed

16.

Goodrich RP (2000) The use of riboflavin for the inactivation of pathogens in blood products. Vox Sang 78(Suppl 2):211–215PubMed

17.

Iseli HP, Thiel MA, Hafezi F, Kampmeier J, Seiler T (2008) Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea 27:590–594. https://doi.org/10.1097/ICO.0b013e318169d698 CrossRefPubMed

18.

Igal V, Pikkel Igal YS, Pikkel YY (2017) Corneal cross-linking as a treatment for fungal keratitis associated with corneal melting. Case Rep Ophthalmol 8:148–151. https://doi.org/10.1159/000456537 CrossRefPubMedPubMedCentral

19.

Shetty R, Nagaraja H, Jayadev C, Shivanna Y, Kugar T (2014) Collagen crosslinking in the management of advanced non-resolving microbial keratitis. Br J Ophthalmol 98:1033–1035. https://doi.org/10.1136/bjophthalmol-2014-304944 CrossRefPubMed

20.

Li Z, Jhanji V, Tao X, Yu H, Chen W, Mu G (2013) Riboflavin/ultravoilet light-mediated crosslinking for fungal keratitis. Br J Ophthalmol 97:669–671. https://doi.org/10.1136/bjophthalmol-2012-302518 CrossRefPubMed

21.

Mohan M, Panda A, Gupta SK (1989) Management of human keratomycosis with miconazole. Aust N Z J Ophthalmol 17:295–297CrossRefPubMed

22.

Shi W, Li S, Liu M, Jin H, Xie L (2008) Antifungal chemotherapy for fungal keratitis guided by in vivo confocal microscopy. Graefes Arch Clin Exp Ophthalmol 246:581–586. https://doi.org/10.1007/s00417-007-0719-x CrossRefPubMed

23.

Das S, Samant M, Garg P, Vaddavalli PK, Vemuganti GK (2009) Role of confocal microscopy in deep fungal keratitis. Cornea 28:11–13. https://doi.org/10.1097/ICO.0b013e318181cff7 CrossRefPubMed

24.

Campoy S, Adrio JL (2017) Antifungals. Biochem Pharmacol 133:86–96. https://doi.org/10.1016/j.bcp.2016.11.019 CrossRefPubMed

25.

Wang JY, Wang DQ, Qi XL, Cheng J, Xie LX (2018) Modified ulcer debridement in the treatment of the superficial fungal infection of the cornea. Int J Ophthalmol 11:223–229. https://doi.org/10.18240/ijo.2018.02.07 CrossRefPubMedPubMedCentral

26.

Xie L, Zhai H, Shi W (2007) Penetrating keratoplasty for corneal perforations in fungal keratitis. Cornea 26:158–162. https://doi.org/10.1097/01.ico.0000248381.24519.0d CrossRefPubMed

27.

Price MO, Tenkman LR, Schrier A, Fairchild KM, Trokel SL, Price FW, Jr. (2012) Photoactivated riboflavin treatment of infectious keratitis using collagen cross-linking technology. J Refract Surg 28: 706–713 DOI https://doi.org/10.3928/1081597X-20120921-06

28.

Ozdemir HB, Kalkanci A, Bilgihan K, Gocun PU, Ogut B, Karakurt F, Erdogan M (2018) Comparison of corneal collagen cross-linking (PACK-CXL) and voriconazole treatments in experimental fungal keratitis. Acta Ophthalmol. https://doi.org/10.1111/aos.13829

29.

Kimura K, Orita T, Nomi N, Fujitsu Y, Nishida T, Sonoda KH (2012) Identification of common secreted factors in human corneal fibroblasts exposed to LPS, poly(I:C), or zymosan. Exp Eye Res 96:157–162. https://doi.org/10.1016/j.exer.2011.10.015 CrossRefPubMed

30.

Vajpayee RB, Shafi SN, Maharana PK, Sharma N, Jhanji V (2015) Evaluation of corneal collagen cross-linking as an additional therapy in mycotic keratitis. Clin Exp Ophthalmol 43:103–107. https://doi.org/10.1111/ceo.12399 CrossRefPubMed

31.

Papaioannou L, Miligkos M, Papathanassiou M (2016) Corneal collagen cross-linking for infectious keratitis: a systematic review and meta-analysis. Cornea 35:62–71. https://doi.org/10.1097/ICO.0000000000000644 CrossRefPubMed

32.

Spoerl E, Wollensak G, Seiler T (2004) Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res 29:35–40. https://doi.org/10.1080/02713680490513182 CrossRefPubMed

33.

Hovakimyan M, Guthoff RF, Stachs O (2012) Collagen cross-linking: current status and future directions. J Ophthalmol 2012:406850. https://doi.org/10.1155/2012/406850 CrossRefPubMedPubMedCentral

34.

Wang F (2008) UVA/riboflavin-induced apoptosis in mouse cornea. Ophthalmologica 222:369–372. https://doi.org/10.1159/000151247 CrossRefPubMed

35.

Pouget JP, Douki T, Richard MJ, Cadet J (2000) DNA damage induced in cells by gamma and UVA radiation as measured by HPLC/GC-MS and HPLC-EC and Comet assay. Chem Res Toxicol 13:541–549CrossRefPubMed

36.

Hiraku Y, Ito K, Hirakawa K, Kawanishi S (2007) Photosensitized DNA damage and its protection via a novel mechanism. Photochem Photobiol 83:205–212. https://doi.org/10.1562/2006-03-09-IR-840 CrossRefPubMed

37.

Wollensak G, Spoerl E, Reber F, Seiler T (2004) Keratocyte cytotoxicity of riboflavin/UVA-treatment in vitro. Eye (Lond) 18:718–722. https://doi.org/10.1038/sj.eye.6700751 CrossRef

38.

Wollensak G, Sporl E, Reber F, Pillunat L, Funk R (2003) Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro. Ophthalmic Res 35:324–328 DOI 74071CrossRefPubMed

39.

Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T (2007) Safety of UVA-riboflavin cross-linking of the cornea. Cornea 26:385–389. https://doi.org/10.1097/ICO.0b013e3180334f78 CrossRefPubMed

40.

Mazzotta C, Balestrazzi A, Traversi C, Baiocchi S, Caporossi T, Tommasi C, Caporossi A (2007) Treatment of progressive keratoconus by riboflavin-UVA-induced cross-linking of corneal collagen: ultrastructural analysis by Heidelberg Retinal Tomograph II in vivo confocal microscopy in humans. Cornea 26:390–397. https://doi.org/10.1097/ICO.0b013e318030df5a CrossRefPubMed

41.

Hafezi F (2011) Limitation of collagen cross-linking with hypoosmolar riboflavin solution: failure in an extremely thin cornea. Cornea 30:917–919. https://doi.org/10.1097/ICO.0b013e31820143d1 CrossRefPubMed

42.

Raiskup F, Spoerl E (2013) Corneal crosslinking with riboflavin and ultraviolet A. Part II. Clinical indications and results. Ocul Surf 11:93–108. https://doi.org/10.1016/j.jtos.2013.01.003 CrossRefPubMed

43.

Rahman MR, Johnson GJ, Husain R, Howlader SA, Minassian DC (1998) Randomised trial of 0.2% chlorhexidine gluconate and 2.5% natamycin for fungal keratitis in Bangladesh. Br J Ophthalmol 82:919–925CrossRefPubMedPubMedCentral

44.

Foster CS, Lass JH, Moran-Wallace K, Giovanoni R (1981) Ocular toxicity of topical antifungal agents. Arch Ophthalmol 99:1081–1084CrossRefPubMed

45.

Allan BD, Dart JK (1995) Strategies for the management of microbial keratitis. Br J Ophthalmol 79:777–786CrossRefPubMedPubMedCentral

46.

Zloty P, Villavicencio O, Belin MW (2013) Aggressive debridement improves outcome of fungal keratitis. Asia Pac J Ophthalmol (Phila) 2:217–220. https://doi.org/10.1097/APO.0b013e3182993f4b CrossRef

47.

McGrath LA, Lee GA (2014) Techniques, indications and complications of corneal debridement. Surv Ophthalmol 59:47–63. https://doi.org/10.1016/j.survophthal.2013.03.004 CrossRefPubMed

48.

Chan E, Snibson GR, Sullivan L (2014) Treatment of infectious keratitis with riboflavin and ultraviolet-A irradiation. J Cataract Refract Surg 40:1919–1925. https://doi.org/10.1016/j.jcrs.2014.09.001 CrossRefPubMed

Title: Evaluation of corneal cross-linking as adjuvant therapy for the management of fungal keratitis
Authors: Anji Wei
Kaidi Wang
Yan Wang
Lan Gong
Jianjiang Xu
Tingting Shao
Publication date: 01-07-2019
Publisher: Springer Berlin Heidelberg
Published in: Graefe's Archive for Clinical and Experimental Ophthalmology / Issue 7/2019
Print ISSN: 0721-832X
Electronic ISSN: 1435-702X
DOI: https://doi.org/10.1007/s00417-019-04314-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Evaluation of corneal cross-linking as adjuvant therapy for the management of fungal keratitis

Abstract

Purpose

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 7/2019

Progression of vascular changes in macular telangiectasia type 2: comparison between SD-OCT and OCT angiography

Is conversion of decimal visual acuity measurements to logMAR values reliable?

Effects of home reading training on reading and quality of life in AMD—a randomized and controlled study

Central retinal venous pressure is higher than intraocular pressure during amateur trumpet playing

Usefulness of the dacryoscintigraphy in patients with nasolacrimal duct obstruction prior to endoscopic dacryocystorhinostomy

Aflibercept with adjuvant micropulsed yellow laser versus aflibercept monotherapy in diabetic macular edema