Fungal Keratitis

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Fungal keratitis or keratomycosis refers to an infective process of the cornea caused by any of the multiple pathologic fungi capable of invading the ocular surface. It is most typically a slow, relentless disease that must be differentiated from other types of corneal conditions with similar presentation; especially its bacterial counterpart, which accounts for the majority of the microbial corneal infections.

Fungal ulcer.jpeg

Disease Entity[edit | edit source]

Fungal Keratitis

Disease[edit | edit source]

Fungal keratitis is a serious ocular infection with potentially catastrophic visual results. Caused by any of the many species of fungi capable of colonizing human tissue, its occurs worldwide and its incidence is increasing in frequency.

Etiology[edit | edit source]

The list covers many fungi including but not limited to yeasts of Candida spp., filamentous with septae such as Aspergillus spp.,Fusarium spp.,Cladosporium,spp.,Curvularia, and non septated such as Rhizopus. Bare in mind thad any agent capable of infecting humans is a potential infectious agent, especially if the host has a debilitating disease.

Risk Factors[edit | edit source]

Risk factors include trauma, ocular surface disease, and topical steroid use. Risks and type of fungi also might vary by geographic location and climate1-7. In warmer climates the rule is that the most common organisms are filamentous fungi, like Fusarium spp and Aspergillus spp. with a strong relationship to trauma. Reports from Brazil show the most common isolates in descending order were Fusarium spp in 67%, Aspergillus spp in 10.5%, and Candida spp in 10%. About 40% of the infections were related to trauma.1

In the northern USA, corneal infection by fungus was, until recently, more common in debilitated or immunocompromised patients and the causative organism being a yeast, such as Candida albicans. Filamentous fungi in these latitudes were then rarely reported. A few years ago a breakout of Fusarium keratitis associated to a type of contact lens solution8 displaced yeasts as the most common fungal corneal infection in some areas. This trend persists in the most recent epidemiological reports. Still they are, in most cases, related to contact lens use. It should be noted that the incidence of contact lens-related fungal keratitis was increasing before the Fusarium outbreak.

This new distribution means that we no longer can rely on the geographical distribution only to initiate empirical treatment. Broad-spectrum treatment should be administerd once there is a strong probability of a mycotic infection.

General Pathology[edit | edit source]

Even thought fungi can be classified as a kingdom due to their complexity and unique characteristics, a simple practical classification for ocular infection is used. Under this method, morphology and type of reproductive method define the type of fungi. They are classified for our purpose as yeast, filamentous septated pigmented and non-pigmented and filamentous without septae. Fungi are present worldwide and can be part of the ocular flora. Are eukaryotic with a defined nucleus surrounded by a membrane. Are either saprophytic, free organisms living out of decaying organic matter or pathologic, those that need a living host for perpetuation.

Pathophysiology[edit | edit source]

The infection probably starts when the epithelial integrity is broken either due to trauma or ocular surface disease and the organism gains access into the tissue and proliferates. Proteolitic enzymes, fungal antigens and toxins are liberated into the cornea with the resulting necrosis and damage to its architecture thus compromising the eye integrity and function.

Primary prevention[edit | edit source]

Wearing safety glasses while gardening will diminish the risk of ocular trauma, also general hygiene, proper contact lens care and avoidance of nonessential steroid use should diminish the probability of mycotic infection.

Diagnosis[edit | edit source]

A high degree of suspicion from the physician accounts for early diagnosis and treatment, which are paramount for a successful resolution of the fungal keratitis. Corneal ulcers unresponsive to broad-spectrum antibiotics, the presence of satellite lesions, scanty secretions in a large ulcer are some signs that should raise flags to the attending professional about the possibility of a mycotic agent.

History[edit | edit source]

Blurred vision, redness, tearing, photophobia, pain, foreign body sensation and secretions related to trauma, ocular surface disease and or topical steroid use.

Physical examination[edit | edit source]

After establishing the patients general condition the examiner should look for evidence of ocular surface disease. Determine the amount and type of secretions and lid swelling,. The upper eyelid should be everted to exclude a retained foreign body. Should measure the size and depth of the lesion as well as the presence of satellite lesions. Also the intraocular pressure should be ascertained. Anterior chamber reaction and evidence of hypopyon recorded. Vitreous reaction if present may suggest intraocular spread of the disease.

Signs[edit | edit source]

With filamentary fungi the corneal lesion have a white/gray infiltrate with feathery borders. There might be satellite lesions with hypopyon and conjunctival injection as well as purulent secretions. Ulcers caused by yeast are plaque like and slightly more defined, similar to bacterial keratitis.

Symptoms[edit | edit source]

Symptoms are similar to any corneal infection including blurred vision, redness, tearing, photophobia, pain, foreign body sensation and secretions. In some cases the lesion are rather indolent which help to delay the diagnosis and hence the treatment. Always be suspicious after trauma with vegetable matter.

Clinical diagnosis[edit | edit source]

Under the slit lamp, early in the evolution the lesion might look like an unhealed corneal abrasion with scanty infiltrates and no secretions. With time the ulcer develops thicker infiltrates and fuzzy margins. The presence of satellite lesions strongly suggests a fungal infection. Redness and periocular edema are also common. This combined with a history of trauma, especially with vegetable matter, ocular surface disease or chronic use of topical steroids should alert about the possibility of a mycotic etiology.

Diagnostic procedures[edit | edit source]

Corneal scrapings are taken from deep into the lesion with a surgical blade or sterile spatula. To perform a corneal biopsy a dermatological 2mm punch can be used.

Laboratory test[edit | edit source]

For a definitive diagnosis scrapings taken from deep into the lesion should be made and inoculated in Sabouraud agar. The shortcoming is that it could take up to 3 weeks to grow and identify the organism. For a faster result, smears with special stains such as Gomori, PAS, acridine orange, calcofluor white or KOH should be performed. The drawback is that not all laboratories can handle those, so, again we might need to rely on the patient’s evolution and the physician’s clinical acumen. If all labs are negative consider a corneal biopsy.

Differential diagnosis[edit | edit source]

Fungal infections can mimic any microbial keratitis; Bacteria, which is the most common cause of corneal infections; Acanthamoeba, related to swimming with contact lenses and or the use of tap water in their cleaning, Herpetic keratitis of which recurrences are frequent. Retained foreign body, sterile infiltrates, and marginal ulcers due to Staphylococcal hypersensitivity and chronic epithelial defect should be ruled out. Again a high index of suspicion is important for it diagnosis.

Management[edit | edit source]

In general, management consist of medical therapy with the use of topical and or systemic anti-fungal medications alone or in combination with surgical treatment.

General treatment[edit | edit source]

Topical antifungals, either commercially available or compounded from systemic preparation into eye-drops are the backbone for the management of fungal keratitis. In resistant cases addition of systemic antifungal have shown effectiveness. If those fail conjunctival flaps , lamellar or penetrating keratoplasty might be needed.

Medical therapy[edit | edit source]

Fungal ulcers are inherently difficult to treat. The diagnosis is often delayed; medications available for ocular therapy are limited and they are deficient in their ability to penetrate deep into the cornea. The mainstay of treatment is the use of antifungal drops but only a polyene, natamycin 5%, is FDA approved and commercially available for topical ocular use. Also, due to the rarity of the diagnosis it is sometimes available only as a special order. Furthermore, the complexity of the disease and possible visually devastating outcomes require a rather aggressive approach to its treatment. Hence, many other antimycotics are used to fight this infection. In these eye drops the intravenous medication is diluted into such concentration that it provide enough medication to eradicate the organism and at the same time is tolerated by the eye.

Prior to the development of natamycin the most commonly used antifungal was amphotericin b, a polyene, in a 0.15% dilution in sterile water (one 50mg vial of amphotericin b diluted in 30cc sterile water gives a 0.166% dilution). It is still used today alone and in combination with natamycin with relatively good results. Since they both are readily available is a good choice as initial therapy.

Voriconazole, a triazole antifungal agent derived from fluconazole, can be used either topically at 1% dilution, orally at 400 mg twice a day and even has being injected in the corneal stroma around the fungal lesion (50 micrograms/0.1 ml)10-12.

Oral posaconazole, a new generation triazole has been successful eradicating deep infections of resistant Fusarium13.Subconjuctival antifungals are not generally used because the produce severe pain and some might even induce tissue necrosis.

Other antifungals available include the azoles like miconazole, clotrimazole ketoconazole, posaconazole, and fluconazole and the echinocandin antifungal agents caspofungin, and micafungin. The echinocandins are not active against Fusarium.

Medical follow up[edit | edit source]

All corneal infections should be followed daily until there is a marked improvement. Since fungal infections run a protracted course, their follow up is longer and after a few days the interval between evaluations increases according to its progress. Complete healing might take weeks and even months. The intraocular pressure should be closed monitored during the episode. It should be noted that epithelialization does not necessary means that the ulcer is healing. In fact it might hinder the penetration of the fungicide. Confocal microscopy might be an effective additional method to follow the success or failure of the therapy. It does so by direct examination of the organism, inflammation, and corneal stromal cells.14

Surgery[edit | edit source]

Periodic debridement is commonly used in the management fungal keratitis. The procedure removes necrotic tissue, diminishes the organism load; but mostly it enhances the penetration of the drugs. It can be performed every 24 to 48 hours.

If everything fails a conjunctival flap might deter the infection if there is no response then a lamellar or penetrating keratoplasty could be needed. If there is perforation, a patch graft or aa therapeutic transplant should be performed. The infected cornea should be sent for cultures and pathological evaluation. It is performed in the usual manner but it should extend about 1 to 1.5mm beyond the margins of the lesion.

Surgical follow up[edit | edit source]

Close follow up for at least 2 weeks with topical antimycotics is recommended. Systemic medication may be added as well. If the edges of the specimen are found by pathology to have organisms the use of topical and systemic antifungals should be extended.

Complications[edit | edit source]

Adverse results range from mild to severe corneal scarring, corneal perforation, anterior segment disruption and glaucoma up to endophthalmitis resulting in evisceration.

Prognosis[edit | edit source]

The aftermath of fungal keratitis can be dismal . There is severe visual loss in 26% to 63% of patients. Fifteen to twenty percent may need evisceration. Penetrating keratoplasty was performed in 31 to 38%.1,15

Additional Resources[edit | edit source]

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References[edit | edit source]

1) Ibrahim MM; Vanini R; Ibrahim FM; Fioriti LS; Furlan EM; Provinzano LM; De Castro RS; de Faria E Sousa SJ; Melani Rocha E Epidemiologic aspects and clinical outcome of fungal keratitis in southeastern Brazil. Eur J Ophthalmol. 2009; 19(3):355-61 (ISSN: 1120-6721)

2) Gopinathan U; Garg P; Fernandes M; Sharma S; Athmanathan S; Rao GN The epidemiological features and laboratory results of fungal keratitis: a 10-year review at a referral eye care center in South India. Cornea. 2002; 21(6):555-9 (ISSN: 0277-3740)

3) Thew MR; Todd B Fungal keratitis in far north Queensland, Australia. Clin Experiment Ophthalmol. 2008; 36(8):721-4 (ISSN: 1442-9071)

4) Ritterband DC; Seedor JA; Shah MK; Koplin RS; McCormick SA Fungal keratitis at the New York Eye and Ear Infirmary. Cornea. 2006; 25(3):264-7 (ISSN: 0277-3740)

5)A) Jurkunas U; Behlau I; Colby K Fungal keratitis: changing pathogens and risk factors. Cornea. 2009; 28(6):638-43 (ISSN: 1536-4798)

6)Iyer SA; Tuli SS; Wagoner RC Fungal keratitis: emerging trends and treatment outcomes. Eye Contact Lens. 2006; 32(6):267-71 (ISSN: 1542-2321)

7)Galarreta DJ; Tuft SJ; Ramsay A; Dart JK Fungal keratitis in London: microbiological and clinical evaluation. Cornea. 2007; 26(9):1082-6 (ISSN: 0277-3740)

8) Ma SK; So K; Chung PH; Tsang HF; Chuang SK A multi-country outbreak of fungal keratitis associated with a brand of contact lens solution: the Hong Kong experience. Int J Infect Dis. 2009; 13(4):443-8 (ISSN: 1878-3511)

9)Chang DC, Grant GB, O'Donnell K, et al. Multistate outbreak of Fusarium keratitis associated with use of a contact lens solution. JAMA 2006;296:953-963. D) Prakash G;

10)Sharma N; Goel M; Titiyal JS; Vajpayee RB Evaluation of intrastromal injection of voriconazole as a therapeutic adjunctive for the management of deep recalcitrant fungal keratitis. Am J Ophthalmol. 2008; 146(1):56-59 (ISSN: 0002-9394)

11)Thiel MA; Zinkernagel AS; Burhenne J; Kaufmann C; Haefeli WE Voriconazole concentration in human aqueous humor and plasma during topical or combined topical and systemic administration for fungal keratitis. Antimicrob Agents Chemother. 2007; 51(1):239-44 (ISSN: 0066-4804)

12)Bunya VY; Hammersmith KM; Rapuano CJ; Ayres BD; Cohen EJ Topical and oral voriconazole in the treatment of fungal keratitis. Am J Ophthalmol. 2007; 143(1):151-3 (ISSN: 0002-9394)

13)Tu EY, McCartney DL, Beatty RF, Springer KL, Levy J, Edward D Successful Treatment of Resistant Ocular Fusariosis With Posaconazole (SCH-56592) 
Am J Ophthalmol. 2007;143:222-227

14) Shi W; Li S; Liu M; Jin H; Xie L Antifungal chemotherapy for fungal keratitis guided by in vivo confocal microscopy. Graefes Arch Clin Exp Ophthalmol. 2008; 246(4):581-6 (ISSN: 0721-832X)

15)Rondeau N; Bourcier T; Chaumeil C; Borderie V; Touzeau O; Scat Y; Thomas F; Baudouin C; Nordmann JP; Laroche L [Fungal keratitis at the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts: retrospective study of 19 cases] J Fr Ophtalmol. 2002; 25(9):890-6 (ISSN: 0181-5512)