Treating infectious keratitis with CXL is not like treating keratoconus with CXL

Treating infectious keratitis with CXL is not like treating keratoconus with CXL. We recently had to write a letter to the journal, Ophthalmology, to point out the flaws in a recent publication in the journal.

The paper in question used one of the most exciting aspects of corneal cross-linking (CXL), a procedure called photoactivated chromophore for keratitis-CXL, or PACK-CXL, as a method of treating fungal keratitis. In their study, 111 patients received either topical antifungal agents (either natamycin 5% or amphotericin 0.15%) with or without PACK-CXL. However, in the end, they concluded, “there appears to be no benefit of adjuvant CXL in the primary treatment of moderate filamentous fungal ulcers, and it may result in decreased visual acuity.”

We believe they made a basic error which meant that an inadequate amount of UV irradiation (fluence) was applied during PACK-CXL to treat fungal infections.

This paper was flawed. It lacked basic details like baseline ulcer size and UV fluence applied. However, looking at the methods section, they cited the classic keratoconus cross-linking “Dresden protocol” (30 minutes of 0.1% riboflavin instillation, followed by 30 minutes of 3 mW UV illumination for a total fluence of 5.4 J/cm2), so we figured it was safe to assume that was used here.

But the Dresden protocol is totally inadequate for treating infectious keratitis, whether it is bacterial or fungal. To explain why, we need to explore what happens when a cornea is cross-linked.

When stroma that is saturated with riboflavin is hit by a UV photon, the riboflavin gets activated, reacts, generates a reactive oxygen species “ROS” which can cross-link the molecules of the stroma together, or attach the cell membranes and nucleic acids of any pathogens present. But it gets consumed. It’s challenging for UV light to penetrate much deeper, as the riboflavin acts as a shield (that gets consumed) against it penetrating further. This is good in many respects, as it protects the corneal endothelial cells at the base of the cornea from being damaged by UV irradiation. But it also means that UV energy absorption decays in a logarithmic manner. The amount of UV energy delivered by the Dresden protocol therefore only cross-links the first 100 µm.

So how deep were these patients’ ulcers? The Methods section says that eyes with “involvement of the posterior one-third of the stroma,” and “central pachymetry less than 350 mm” were excluded, and that 46% and 68% of CXL treated patients (with natamycin and amphotericin, respectively) had ulcer depths of 33–67% of the depth of the stroma.

Let’s do some arithmetic to find what would be the shallowest-possible ulcer depth (and therefore had the greatest chance of successful treatment with a PACK-CXL protocol that treats just the top 100 µm of the cornea).

If the thinnest cornea was 350 µm in the study, and the shallowest ulcer depth range was 33–67%, this means that the ulcer depths range from 111.5–234.5 µm – and therefore thicker corneas would have even deeper ulcers.

Finally, this all assumes that the cornea is a keratoconic one, not one with an ulcer – which is opaque, meaning that it is even harder for UV light to penetrate into the cornea. All in all, this means that even in the best-case scenario, not enough UV energy was delivered into the cornea to treat all of the infection.

We have already shown that PACK-CXL is more effective at killing bacteria when higher UV fluences are used, and we are seeing in our ongoing clinical trial that the effectiveness of PACK-CXL with a total fluence of 7.2 J/cm² is similar to that of antimicrobial therapy. For these reasons, we believe the authors of this paper used an inadequate fluence to treat these patients’ fungal ulcers.

References

  1. Hafezi F, Torres-Netto EA, Hillen MJP. Re: Prajna 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. Aug 13. Online ahead of print.
  2. Prajna NV, Radhakrishnan N, Lalitha P, et al. A randomized clinical trial evaluating the effect of adjuvant cross-linking on outcomes in fungal keratitis. Ophthalmology. 2020;127: 159e166.
  3. Kling S, Hufschmid FS, Torres-Netto EA, et al. High fluence increases the antibacterial efficacy of PACK cross-linking. Cornea. 2020;39:1020e1026.

The ELZA Institute

EN | DE

Augeninstitut ELZA
4.7
Based on 95 reviews
powered by Google
Thunder Shiviah
Thunder Shiviah
14:05 23 Nov 21
After some research on local options I decided to go with ELZA since it stood out as the best. The operation and the... post-operation recovery went extremely smooth (something I was worried about with PRK). Now my vision is much better than I had hoped and I have no side effects such as dry eye or night vision problems. Thank you!read more
Squitieri Elias
Squitieri Elias
12:43 08 Sep 21
Die Behandlungen waren bei mir erfolgreich, alle waren sehr nett und haben mein Leben vereinfacht.Danke
Eliane Bossart
Eliane Bossart
13:01 05 Sep 21
Vor einem Jahr war ich einer ganz verzweifelten Situation und total im Stich gelassen. Meine Augen wurden aufgrund... eines ausgeprägten Kerakotonus immer schlechter, ich hatte Angst und war alleine mit meinen Problemen. Zudem vertrug ich die Kontaktlinsen nur noch ganz schlecht und hatte jeden Tag Schmerzen.Professor Hafezi hat mir mit zwei Operationen wieder das auf Grund der Situation mögliche an Lebensqualität zurückgebracht. Es war ein starpaziöses Jahr mit vielen Entbehrungen aber es hat sich gelohnt! Herzlichen Dank fuer die Unterstützung.read more
Gabriela Meyer
Gabriela Meyer
18:32 22 Aug 21
Ich wurde von meiner Optikerin auf Prof. Dr. Dr. Hafezi aufmerksam gemacht. Es war mir vorher nicht bewusst, dass meine... Augenkrankheit (Keratokonus) operativ mittels Cross Linking behandelt und so gestoppt werden kann. Die Beratung und Behandlung war sehr kompetent und ich fühlte mich jederzeit wohl. Die Operation verlief gut und das Ergebnis ist einwandfrei.read more
Naomi
Naomi
11:38 11 Aug 21
Ich bin sehr glücklich, dass ich das Elza Institute gefunden habe. Ich wurde von anderen Augenärzten abgewiesen, da... meine Augen zu kompliziert/schwierig zu behandeln waren. Prof. Dr. Dr. Hafezi konnte mir jedoch helfen und ich bin sehr glücklich und zufrieden mit dem Resultat. Vielen Dank!read more
Till B
Till B
08:30 19 Jul 21
Ich habe eine überaus kompetente Beratung und Behandlung erlebt. Die gesamte Betreuung war sehr freundlich und... professionell. Herzlichen Dank!read more
Thomas S.
Thomas S.
09:37 07 Jul 21
My left eye had to be operated on because of a cataract. As I had an Artiflex lens implanted a few years ago, it had to... be removed first before a modern lens could be implanted to correct the cataract. Prof. Hafezi treated me in an very competent and friendly manner. I am very happy with the result.read more
Selma A. Rahim
Selma A. Rahim
19:45 02 Jul 21
Dr. Hafezi.. the KING OF CXL🤴
Gianluca Ricci
Gianluca Ricci
12:46 10 Apr 21
Great team and service!
rehaneyecare
rehaneyecare
05:36 08 Apr 21
Excellent surgeon
Steven H.A
Steven H.A
16:13 11 Jan 21
Prof. F. Hafezi s expertise is enormous and he has a very pleasant and calm nature which gives the patient... security.Thank youread more
Online Commande
Online Commande
09:19 05 Dec 20
Totally creepy, very arrogant Prof.He just want your money.It may explain, why this Prof. is not in the center of the... city of Zürich and why he has been thrown away from University of Geneva.read more
Elena Churilova
Elena Churilova
10:06 17 Nov 20
At the moment, 3 months have passed since the moment I made laser vision correction in this clinic. and I can say that... I am happy that I chose this particular clinic and Prof. F. Hafezi. The entire staff of the clinic is very friendly, treats patients with sympathy and patience if they are nervous before surgery (my big gratitude to Aida Alili for all support and patience). The doctor Hafezi and other doctors of the clinic are very professional and ready to explain to you as many times as you need. I can only recommend!read more
Next Reviews
Augeninstitut ELZA
4.7
Based on 95 reviews
powered by Google