EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: To report the outcomes of therapeutic corneal transplant for managing fungal keratitis that is refractory to medical treatment.

Materials and Methods: Retrospective data analyses of the medical records was performed on 17 patients who underwent a therapeutic corneal transplant for severe culture-proven fungal keratitis between October 2006 and August 2013. We evaluated demographics, fungal organism type, surgical data, recurrence presentation, disease course, follow-up, and graft status.

Results: Mean patient age was 53.2 years (range, 33-81 y). The male/female ratio was 12/5. All patients had positive microscopic evaluation and positive culture results for fungal infection. The most common fungal agent was Fusarium sp. (35%). Nine patients reported a history of injury to the cornea and/or contact with plant material or soil. The mean best-corrected visual acuity at the initial visit was 2.45 logMAR unit (range, 0.52-3.10 logMAR unit). The mean follow-up was 14 months (range, 6-76 mo). Four patients underwent evisceration surgery because of graft lysis or uncontrolled recurrent disease. Recurrence of the fungal infection after corneal transplant was seen in 8 patients (47.05%). The graft rejection rate was 18.18%. At the final visit, 5 grafts were clear, 4 were translucent, and 2 were opaque. There were 2 phthisis bulbi owing to catastrophic disease. The mean final best-corrected visual acuity was 1.64 logMAR unit (range, 0.22-3.10 logMAR unit).

Conclusions: Although therapeutic corneal transplant has a higher incidence of infection recurrence and graft failure, it continues to be an effective treatment for uncontrolled, refractory fungal keratitis cases to save the affected eye.

Key words : Eye, Fungal keratitis, Penetrating corneal transplant, Therapeutic corneal transplant.

Infectious keratitis is one of the most significant causes of ocular morbidity and blindness worldwide.¹ There are various pathogens that lead to infectious keratitis including bacteria, virus, protozoa, and fungus. Fungal keratitis is reported to be up to 40% of all microbial keratitis, especially in developing countries, with species most commonly being Fusarium and Aspergillus.^2-4

Fungal keratitis usually follows a trauma or prolonged steroid treatment.⁵ The majority of the cases occur in farmers. Warm and humid climate accelerates the incidence of fungal infection.⁶ Slit lamp examination findings of fungal keratitis consist of corneal ulceration with satellite lesions, patchy deposits behind the cornea, and accompanying hypopyon. In advanced cases, corneal perforation that may lead to infection, ending with endophthalmitis, can occur.⁷

When compared with other infectious keratitis types, managing fungal keratitis is difficult.⁵ Despite recent development of antifungal agents, treating fungal keratitis remains challenging. Therapeutic corneal transplant is performed to manage fungal keratitis patients who are unresponsive to maximal medical therapy or have corneal perforations owing to the infection.^8,9

In the literature, therapeutic corneal transplant has been reported to range in 12% to 38% of fungal keratitis.^10-12 Here, we report our clinical results of refractory fungal keratitis patients who underwent therapeutic corneal transplant surgery to save the eye and treat infection.

Materials and Methods

We retrospectively reviewed the medical records of 17 culture-proven fungal keratitis patients who underwent therapeutic corneal transplant between October 2006 and August 2013 at the Ophthalmology Department, of the Ege University School of Medicine, in Izmir, Turkey. (There were 35 culture-proven fungal keratitis patients during this period, and 17 of these patients underwent a therapeutic corneal transplant.) The demographics, fungal organism type, surgical data, recurrence rate, disease course, best-corrected visual acuity values (logMAR unit), graft outcome, graft rejection, and additional surgeries (if any) were evaluated (Table 1).

Upon arrival, and after obtaining the diagnostic material for microbiological examination, all patients were initiated hourly with topical vancomycin (50 mg/mL) and ceftazidime (50 mg/mL) for presumed bacterial keratitis, and hourly topical fluconazole (2 mg/mL) and oral fluconazole 100 mg twice daily for presumed fungal keratitis. The treatment regimens were revised according to the results of cultures and antibiogram. By the time fungal keratitis was proven by culture, topical vancomycin and ceftazidime drops were replaced with topical moxifloxacin hydrochloride (Alcon LenSx, Inc., Aliso Viejo, CA, USA) every 2 hours. Topical fluconazole (2 mg/mL) for yeast and topical voriconazole (10 mg/mL) for mold fungi were chosen for topical treatment.

Eyes that were unresponsive to appropriate antifungal treatment (any fungal keratitis that did not regress or that showed progression despite appropriate topical antifungal treatment was considered unresponsive) or progressed to corneal melting and perforation, underwent a therapeutic corneal transplant. In all cases, the size of the trephine was chosen to involve all of the diseased corneal area, and the donor cornea was punched 0.25 mm larger than the recipient bed. Interrupted suturation was performed by 10.0 monofilament nylon sutures. In the evidence of purulent materials and fibrotic membrane in the anterior chamber, removal of these materials, angle revision (if needed), and anterior chamber irrigation with 0.2% fluconazole was performed. Topical antifungal treatment was continued for at least 3 months after surgery. Upon completed epithelization after surgery, topical corticosteroids 4 times daily were started to prevent graft rejection. Follow-ups were adjusted according to the ophthalmologic examination findings of each patient.

The mean age of patients was 53.2 years (range, 33-81 y; 12 men, 5 women). The most common fungal agent was Fusarium sp. (35%). Nine patients (52.9%) reported a history of injury to the cornea and/or contact with plant material or soil. One patient receiving immunosuppressive agent had a medical history of severe rheumatoid arthritis. The rest of the patients were unable to provide a cause for their infection. Four of 17 patients (23.52%) had corneal perforation on the initial visit. Seven patients (41.17%) had hypopyon and 4 patients (23.52%) had a corneal infection expanding to the limbus on first examination (Figure 1). The mean best-corrected visual acuity on the initial visit was 2.45 logMAR unit (range, 0.52-3.10 logMAR unit). Immediate corneal transplant surgery (ie, 1-9 d) was performed in cases with corneal perforation or excessive fungal disease. The mean time in our cases between the first visit and the surgery was 15.47 days (range, 1-75 d).

The mean follow-up was 14 months (range, 6-76 mo) for patients who did not undergo evisceration surgery. Four patients (23.52%) underwent evisceration surgery because of graft lysis or uncontrolled recurrent disease. Recurrence of the fungal infection after the corneal transplant was noted in 8 patients (47.05%), and the outcomes of recurrence in each patient are summarized in Table 2. Graft rejection rate was 18.18%. The mean number of corneal transplants for each patient was 1.18 (range, 1-3) and anatomic success was maintained in 11 of 17 patients (64.70%). During the final visit, 5 grafts were clear (Figure 2), 4 were translucent, and 2 were opaque. Two eyes ended up with phthisis bulbi because of catastrophic infection and inflammation. The mean final best-corrected visual acuity was 1.64 logMAR unit (range, 0.22-3.10 logMAR unit).

Fungal keratitis is one of the most devastating ophthalmologic infections. The majority of the fungal keratitis cases have a history of injury to the cornea and/or contact with plant material or soil.⁶ In our case series, trauma history was present in 52.94% of the cases. The most commonly isolated pathogen in this case series was Fusarium sp. (35%), which is in agreement with the literature.¹³

With recent pharmaceutical developments, fungal keratitis can be successfully controlled, especially during the early stages of the disease, with appropriate antifungal agents.^14-22 However, cases that are unresponsive to antifungal treatment require a therapeutic corneal transplant surgery to control the disease and save the eye. In the literature, therapeutic penetrating corneal transplant has been reported to range between 12% and 38% of fungal keratitis.^10-12 Nevertheless, this surgery has disadvantages including a high incidence of graft infection and failure.^6,23-26 The graft survival rate for therapeutic corneal transplant is related with the type of infective agent, the severity of inflammation, surgical timing, donor tissue quality, graft size, pre- and postoperative medical treatment, and perforation existence.²⁷

Unless the cornea is perforated, therapeutic corneal transplant is recommended to be performed 7 to 10 days after initiating antifungal drugs. However, if there is a corneal perforation, corneal transplant should be performed as soon as possible.²⁶ In cases with corneal perforation or excessive fungal disease, we performed a corneal transplant as soon as possible. The mean time in our cases between the first visit and surgery was 15.47 days.

One of the most important causes of treatment failure after therapeutic corneal transplant for fungal keratitis is infection recurrence. In the literature, the rate of fungal recurrence is reported to be between 5% and 14%.^27,28 In this study, the recurrence rate was found to be 47.05%, which is higher than the values reported in the literature.^27,28 Preoperative hypopyon, corneal perforation, and corneal infection expanding to the limbus increase the recurrence rate of fungal keratitis after a corneal transplant.²⁹ In our group of patients, on initial examination, 4 had a corneal perforation, 7 had a hypopyon, and 4 had a corneal infection expanding to the limbus. Moreover, as our clinic is a tertiary center in the region, 8 patients (47.05%) were referred to our clinic at the end stage of the disease—using multiple antibiotics, antiviral, antifungal agents, and steroids. This may be the major reason for the higher recurrence rate and increased surgery requirement among our cases. The surgery rate in our series was 48.57% among all culture-proven fungal keratitis patients, which is higher than that reported in the literature.^10-12

Graft rejection is an expected complication of therapeutic corneal transplant surgery. The rejection rate of therapeutic corneal transplant for fungal keratitis is reported to be 29.60%, which is higher than that of other keratitis types.6 In this study, the graft rejection rate was 18.18%, which is slightly lower than that presented in the literature.^6,25

A larger graft size (≥ 9.00 mm) provides an opportunity to remove larger infected tissue with high anatomic precision but less functional results.³⁰ In this study, smaller graft size (≤ 8 mm) was chosen for corneal transplant surgery, and this preference might be the reason for the high recurrence rate and low rejection rate in our cases.

In patients with preserved eyeballs, corneal graft success was 81.81%, which is consistent with the literature.^6,25 In contrast with graft success, we found a low visual recovery rate in our study group (54.54%; 6 patients). Although improvement of visual acuity after a therapeutic corneal transplant for fungal keratitis is reported to be 88.5%,²⁵ in our study, patients with no gain in visual acuity had additional ocular problems (mature cataract; 2 patients, chronic retinal detachment; 1 patient), which are unrelated to their corneal graft outcome, except for 2 patients with opaque grafts.

In conclusion, early diagnosis and urgent initiation of appropriate antifungal therapy are critical to control fungal keratitis. Refractory fungal keratitis is a therapeutic challenge, as it may progress to corneal perforation and fungal endophthalmitis. Moreover, concomitant inflammation also may result in extensive iris synechia, secondary glaucoma, and extrusion of the intraocular contents.^31-35 Therefore, if the infection does not respond to proper medical treatment, a therapeutic corneal transplant should be considered as an alternative treatment option for refractory fungal keratitis.⁶ A therapeutic corneal transplant also is an effective method for visual rehabilitation and protection of the eye with a proper timing of surgery in severe fungal keratitis.

Volume: 13 Issue: 4 August 2015

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