Topical losartan for treating corneal haze after Pseudomonas keratitis: a case report

Introduction

Corneal scarring is a significant cause of visual impairment worldwide, resulting from various etiologies such as infections, injuries, and inflammatory disorders. Infectious keratitis, particularly due to bacteria like Pseudomonas aeruginosa, is a leading contributor to corneal opacities. The incidence of corneal blindness varies globally, with higher prevalence in regions lacking adequate healthcare resources (1).

Scar formation leads to a loss of cellular transparency and deposition of disorganized extracellular matrix that accompanies corneal fibroblast proliferation, migration, and differentiation into transforming growth factor-β (TGF-β) dependent myofibroblasts (2,3).

TGF-β is a crucial cytokine mediating the development of transient, due to fibroblasts or persistent, due to mature myofibroblasts, corneal opacity (2,4). Moreover, persisting TGF-β pathway activation promotes maturation of myofibroblasts and supports their survival in the stromal tissue (2,4). Defective regeneration of the epithelial basement membrane (EBM) is the key to allowing excessive TGF-β into the stroma to drive the development of myofibroblasts and fibrosis, and repair of the EBM is critical to permanent resolution of the fibrosis (5).

Management strategies for corneal haze aim to reduce scarring and improve visual acuity. Topical corticosteroids are commonly employed to diminish inflammation and prevent scar formation; however, their long-term use is associated with potential side effects, including elevated intraocular pressure (IOP) and increased risk of infection (6,7).

Losartan is a systemic drug used to treat conditions such as hypertension, kidney disease, heart failure, and left ventricular enlargement. Antagonizing angiotensin II receptor, losartan inhibits the extracellular kinase activated through the TGF-β pathway (8,9).

Topical losartan inhibits TGF-β-mediated corneal fibroblast production of collagen type IV after corneal injury throughout the full thickness of the stroma (5,7), penetrating the intact corneal epithelium where the TGF-β pathway promotes development of myofibroblast and their survival (8,10).

Recently, topical losartan has been found to have efficacy in treating patients experiencing persistent haze and in reducing post-surgical (8) or alkali burns-induced corneal scarring (10) in preclinical studies.

To our knowledge, the use of topical losartan for treating corneal haze post-bacterial keratitis has not been previously reported.

This case report presents a patient who had complicated Pseudomonas corneal infection in his right eye developing a severe scar, successfully treated with topical Losartan. We present this article in accordance with the CARE reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-24-31/rc).

Case presentation

A 30-year-old man was referred to Eye Clinic (San Giuseppe Hospital, IRCCS Multimedica, Milan, Italy) for a corneal scar in the right eye due to a Pseudomonas infection occurred 178 days prior to consultation.

In the right eye, the best-corrected visual acuity (BCVA) was 20/40, with a hybrid contact lens [UltraHealth VLT, Carlsbad, CA, USA; 100, base curve (BC) 8.4 mm, F, diameter 14.5 mm, power −5.50 sf], and 20/16 in the left eye with soft contact lens (J&J Oasys, Jacksonville, FL, USA; 1 day, BC 8.5 mm, power −5.50 sf, −1.25 ax, 180°). BCVA with spectacles was 20/80 in the right and 20/20 in the left eye. IOP was 16 and 14 mmHg in the right and left eye, respectively. A significant paracentral stromal haze was detected at the slit lamp (Figure 1) and significant opacity noted on Scheimpflug corneal tomography (Pentacam, Oculus Optikgeräte, Wetzlar, Germany) (Figures 2,3).

Figure 1 Slit lamp biomicroscopy of the patient’s right eye in January 2024 (A) and May 2024 (B), after 4 months of losartan application. A marked reduction in opacity was noted after topical losartan treatment.

Figure 2 Pentacam (Oculus Optikgeräte GmbH) analysis of the right cornea in January 2024 (left column) compared to May 2024 (right column) shows topometric measurements before and after treatment with topical losartan, respectively.

Scheimpflug corneal tomography was also used to obtain the following topometric parameters in the right eye: K1 37.4 D, K2 48.7 D, astigmatism −11.3 D, and Kmax (front) 59.8 D. Corneal thickness was 303 and 570 μm in the right and left eye, respectively (Figure 2A).

Patient was on topical dexamethasone 0.2% four times per day for 48 days in the right eye, but with a long history of topical steroid application. He was firstly treated with subconjunctival betamethasone 1.5 mg/2 mL 42 days after the acute episode, once the infection was considered resolved, and from then with topical dexamethasone drops 0.2% eight times a day, with slowly tapering to four times daily until the day of his presentation to Eye Clinic.

The patient was complaining of his right visual acuity and was highly motivated to improve it, but was not keen to have surgery. He reported stable visual acuity and no improvement in the last 2 months.

For this reason, he was advised about the possibility of off-label treatment with topical losartan drops in his right eye and patient agreed to undergo the therapy, which was initiated around 2 months after the resolution of the infectious process. Pure losartan potassium was diluted in balanced saline solution to obtain a 0.8 mg/mL solution. The regimen consisted of one drop in the right eye 6 times/day, along with frequent preservative-free artificial tears. Topical dexamethasone 0.2% treatment was discontinued due to concerns about opacification of the crystalline lens and prolonged elevation in IOP.

After 4 months of topical losartan treatment, combined with artificial drops, the patient reported no adverse effects and a significant improvement of the right eye vision. BCVA in the right eye had increased to 20/25 with the same hybrid contact lens (UltraHealth VLT; 100, BC 8.4 mm, F, diameter 14.5 mm, power −5.50 sf) and to 20/40 with spectacles. Vision acuity in the left eye was stable. IOP was under control in both eyes.

A significant clinical improvement of the opacity was observed at the slit lamp examination (Figure 1B).

Topometric parameters in the right eye were K1 36.8 D, K2 47.6 D, astigmatism −10.8 D, Kmax (front) 54.3 D, and pupil center corneal 408 μm showing a significant reduction in the Kmax value and significant increase in pupillary corneal thickness (Figure 2B).

Corneal optical densitometry was assessed by Scheimpflug corneal tomography (Figure 3) using backward light-scatter. On initial presentation, corneal densitometry, estimated in two different points on the corneal scar, was 71.8 and 72.3 grayscale units (GSU; 0–100 light scattering; 0= maximal transparency/optically clear cornea; 100= minimal transparency/total corneal opacification) (Figure 3A). After 4 months of losartan use, corneal densitometry, assessed in the same two points of the corneal scar, decreased to 48.8 and 49.0 GSU, respectively (Figure 3B). No adverse or unanticipated events were observed during the study. The plan was to extend the treatment duration to 9 to 12 months, with close monitoring to assess the ongoing response and manage the discontinuation process.

Figure 3 Corneal densitometry (Scheimpflug images). Pentacam (Oculus Optikgeräte) analysis of the right cornea in January 2024 (A) before topical losartan treatment compared with May 2024 (B) after 4 months of topical losartan use. The top image shows corneal densitometry, estimated in two different points on the corneal scar, of 71.8 and 72.3 GSU respectively, gradually reduced to 48.8 and 49.0 GSU in the same points, after 4 months of topical losartan treatment. GSU, grayscale units.

All procedures performed in this work were in accordance with the ethical standards of the institutional research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this manuscript and any accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Corneal ulcers often result from infections like bacterial keratitis. They can lead to significant scarring, impairing vision. Traditional treatments, such as topical steroids, have limited effectiveness and potential side effects, including increased IOP, cataract formation, and local immunosuppression with prolonged use (11). Therefore, it is crucial to find alternatives to treat clinically significant corneal opacities.

Corneal wound healing is a complex process that should restore the stromal tissue both structurally and functionally (5).

Corneal injury induces apoptosis of the anterior keratocytes and a concurrent high-rate proliferation of keratocytes in the stromal tissue (12). The keratocytes and the precursor cells recruited from the bone marrow become fibroblasts, repopulating the damaged corneal tissue (12). The transient corneal haze is due to the presence of fibroblasts given the opaque nature of these cells, producing less amount of crystallin (12). However, the subsequent maturation of myofibroblasts make the corneal haze clinically significant. The opacity of the myofibroblasts and the excessive production of abnormal extracellular matrix substantially contribute to the haze that we observe in our patients (13).

Numerous studies have shown that TGF-β isoforms are critical regulators of the development and survival of myofibroblasts, playing a crucial role in the formation and resolution of stromal scarring and fibrosis (2,14,15). TGF-β1 and TGF-β2 can originate from several sources, including tears, corneal epithelium, corneal endothelium, and aqueous humor (2,3,8). Thus, after a corneal injury, TGF-β drives myofibroblast development and maintains their survival (16). Pharmacological agents that inhibit TGF-β signaling could be effective candidates for modulating myofibroblasts and the stromal fibrosis (17).

Losartan, an antagonist of angiotensin-converting enzyme II receptor, has been extensively shown to prevent the activation of TGF-β signaling pathway, therefore modulating fibrosis in several organs (5,18-23).

Wilson and colleagues introduced the concept of regulating myofibroblast maturation and long-term survival to obtain a functional corneal wound healing and restoration of corneal clarity using topical losartan (11). The regeneration of the EBM through the coordinated efforts of the epithelium and corneal fibroblasts after losartan triggers myofibroblast apoptosis is critical in the elimination of fibrosis and prevention of recurrence after the topical losartan is stopped (5,11).

Recently, both pre-clinical rabbits (1,8,10) and clinical studies (17,24) have confirmed the efficacy and safety profile of topical losartan used as both preventive and active treatment for corneal fibrosis and scarring in a variety of clinical scenarios, such as corneal injuries, chemical burns, trauma, and post-surgical complications.

Sampaio et al. demonstrated that topical 0.1 mg/mL losartan six times per day decreased the development of myofibroblast induced by TGF-β signaling activation, and the fibrosis in the stromal tissue following descemetorhexis in a rabbit model (8,25). In another study, the same authors showed an additive effect of steroid and losartan, inhibiting the maturation of stromal myofibroblast and scar formation in the setting of alkali chemical injury (10). Martinez et al. investigated the effects of topical losartan treatment on rabbits with radial, nearly full-thickness incisions extending from the center of the cornea to the limbus (26).

The most significant finding of this study was that topical losartan treatment did not interfere with the closure of corneal incisions. Additionally, topical losartan at a concentration of 0.8 mg/mL, applied six times daily, was highly effective in reducing opacity due to fibrosis around the incision within 15 days of starting treatment (26).

The last two case reports evaluated the efficacy of topical losartan in humans: they showed an improvement of visual acuity and a reduction of corneal haze developed after two different complicated corneal surgical procedures, laser-assisted in situ keratomileusis (LASIK) and cross-linking, respectively (17,24).

As Wilson postulated, losartan potentially works by inhibiting the activation of extracellular signal-regulated kinase (ERK) in TGF-β signal transduction, which regulates myofibroblast viability and function (27).

In our case, we noticed a progressive improvement in vision and a reduction in fibrotic corneal haze after initiating topical losartan therapy. These findings corroborate the hypothesis of the anti-fibrotic use potential of losartan, leading to patient’s functional recovery. Pentacam-Scheimpflug system allowed us to quantify the corneal opacity, ensuring a way for physicians to measure the amount of backscattered light caused by a patient’s corneal haze and indirectly evaluate corneal transparency, objectively.

The elevated corneal densitometry readings before losartan treatment observed in this case are consistent with those reported in cases of cornea scars (28,29). Furthermore, this case demonstrates that final densitometry does not correlate with final visual outcomes (28,29).

This case highlights the potential of topical losartan to regulate corneal fibrotic haze following bacterial keratitis. To the best of our knowledge, this case represents the first human case of corneal haze from bacterial keratitis treated with topical losartan.

However, severe microbial ulcers that cause significant excavation of the corneal stroma typically necessitate lamellar or penetrating keratoplasty. While topical losartan may help reduce fibrotic opacity in these severe cases, it is not sufficient to restore the normal corneal morphology. Consequently, corneal transplantation remains essential for vision restoration in such advanced cases.

Limitations

This case report, being a single-patient study, is inherently limited in its ability to generalize findings to a broader population. Additionally, the absence of long-term follow-up data restricts our understanding of the sustained efficacy and potential delayed adverse effects of topical losartan in treating corneal haze following bacterial keratitis. To establish more definitive conclusions, further robust studies, such as randomized clinical trials with extended follow-up periods, are warranted.

Conclusions

Losartan may represent a promising and innovative alternative to current standard treatments for corneal haze fibrosis following bacterial infections. We hope this report will contribute to encourage further research evaluating the role of topical losartan in preventing the development of corneal scars, a sight-threatening corneal morbidity.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-24-31/rc

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-24-31/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-24-31/coif). P.L.S. serves as an unpaid editorial board member of Annals of Eye Science from November 2024 to December 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this work were in accordance with the ethical standards of the institutional research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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