Fungal keratitis

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Introduction

Fungal keratitis, also known as keratomycosis, is a severe inflammation in the cornea of the eye after exposure to certain fungi. General keratitis occurs frequently with bacterial organisms, but fungal keratitis is also becoming prevalent-forming about 50% of keratitis . Although mainly found in tropical or temperate climates such as India, Ghana, Nepal, and Burma, more serious cases have emerged in other regions of the world, including the United States, mainly in South Florida. Annually, 30,000 new cases are reported in the U.S , , . Early and accurate diagnosis is key to successful treatment, specifically in identifying the pathogenic microorganism. However, fungal keratitis is challenging to treat because most anti-fungal treatments are ineffective against these fungal infections, especially in its advanced stages. Optometrists or ophthalmologists who diagnose the infection often resort to a combination of topical or systemic treatments. There is controversy surrounding the appropriate medications to use since treatment depends on the species and degree of infection. Progressive cases require surgical procedures to remove the pathogen or replace part of the cornea. Prolonged treatment or no treatment leads to poor vision or vision loss, adversely affecting the young, working adult population2. This is largely an economic and public health concern, especially in developing countries.

Pathology

The risk factors and causative pathogens involved in fungal keratitis vary depending on geographical location. Local climate, occupational environment, and urbanization conditions all affect infection dynamics. The highest risk is ocular trauma or exposure to vegetative material in farms and soil, mainly in the rural areas or in developing countries4. The other major risk factor is extended contact lens wear in developed countries. In the United States, there is a 37% chance of patients contracting fungal keratitis with contact lens use, than a 25% chance of trauma infection. In comparison, 40% of India’s microbial keratitis cases are due to fungal trauma infection2. Other risks include use of topical steroids and pre-existing corneal surface diseases or systemic diseases (diabetes)1, . The different risk factors are also associated with different fungi pathogens. Candida spp. and Fusarium spp. are frequently related to systemic diseases, while ocular trauma is usually caused by Aspergillus spp. and Fusarium spp. The use of topical steroids are linked with Candida spp., Acremonium spp. and Aspergillus spp., but contact lens-related infections are mainly due to Candida spp. and Fusarium spp1, . There are additional pathogens emerging such as the Trichophyton species, but those are rare cases that still need further investigation to determine their pathogenicity.

Organisms

The four main fungal genera associated with fungal keratitis are: Candida, Aspergillus, Fusarium, and Acremonium1,2, . Filamentous fungi, Aspergillus (A. flavus, A. fumigatus), Fusarium (F. oxysporum, F. solani), and Acremonium, are the major cause of fungal keratitis found in tropical and subtropical regions. However, Candida (yeast like fungi infections) is predominant in developed countries and temperate climates, especially Candida albicans.
Candida albicans grows as yeast cells and commensally lives in the human microbiome. This fungus is also the causative agent in human oral and genital infections as it lives in the mouth and gastrointestinal tract. C. albicans are usually spherical unicellular yeast cells but will be dimorphic or turn into a multicellular filamentous fungi when infecting host tissues .
Aspergillus is a filamentous fungal genus consisting of hundreds of molds found in decaying plants and soil. A majority of fungal keratitis infections initiate from A. fumigatus. The second most common species is A. flavus . Aspergillus colonies are flat, yellow and have a powdery texture. Both species have optimal growth temperatures around normal body temperatures, but since they are also spore forming, they are also able to withstand extreme temperatures. A. flavus particularly thrives in hot and dry environments therefore being a prime threat in Southeast Asia, Africa, and the Middle East .
Fusarium spp. are commonly found in plant crops and water sources worldwide and is the most dominant in southern India and Florida. F. oxysporum and F. solani are the two pathogenic species of fungal keratitis6.
Acremonium is a large filamentous fungal genus of approximately 150 species found in plant soil and debris . These are slow-growing fungus that appears glossy with segmented branched or intertwined thin hyphae and long, narrow phialides that form conidia (small non-motile spores).


Pathophysiology

The mechanism of infection for all fungi involved in keratitis is universal. The organisms mainly affect the corneal epithelium, corneal stroma, and the anterior chamber. The airborne spores or conidia germinate into hyphae and directly penetrate the corneal surface through the basement membrane and into the anterior chamber11. Fungi cause physical damage to the cornea by creating lesions with replicated machinery. In response to the invasion, an innate immune response damages tissues and leaves scars that result in opaque ulcers, pain, and eye discharge2. Contact lens fungal keratitis has a similar infection route when airborne and can settle in lens cases, forming a biofilm on the lens and case. Once the lens comes into contact with the cornea, the hyphae can then manifest into an infection10. Symptoms may occur anytime within 24 hours or up to 20 days depending on the type of fungal pathogen. Fungi can also release mycotoxins that suppress the host immune system. Candida spp. also release proteases in addition to mycotoxins, enhancing their invasiveness . If the fungi penetrate past the anterior chamber into the sclera (outer white portion of the eye), removing the organism is extremely difficult and dangerous.

Clinical Features

Symptoms of Infection

In terms of keratitis, fungal keratitis is one of the most challenging infections to diagnose due to its similarity with bacterial keratitis. Common symptoms include red and painful inflammation of the eye, blurred vision, and discharge from the tear ducts2. Corneal ulcers may also result with filamentous fungal contamination. These ulcers can appear white and opaque with feathery edges, stromal infiltrates and surrounding hyphae lines. The extended hyphae line is a clear distinction between bacterial keratitis and fungal keratitis5, 8. There may also be satellite lesions (secondary lesions) as a result of the penetration and endothelial plaque made of leukocytes present underneath the lesions. Those experiencing the symptoms above are advised to see an appropriate eye care professional immediately.

Diagnosis

A clinical examination for diagnosis is not enough to determine the proper treatment since fungal keratitis is often misinterpreted for other eye infections. It is crucial to accurately identify the pathogen using laboratory cell culture and tissue sampling. Tissue swabbing on the surface of the cornea is ideal to obtain a sample of the pathogen but deemed ineffective since the pathogen may penetrate into deep layers of the cornea. Corneal scraping with a sterile spatula or blade is recommended to obtain a sample. If the potential cause is due to contact lens wear, samples could be taken from the contact lens, contact lens case, and solution. In order to determine if the pathogen is fungus or bacterial species, a preliminary Gram stain of the sample is performed to obtain basic characteristics of the organism. This is a common approach for patients suspected with infectious keratitis. If the organism is a fungus, a gram stain would not work and additional tests would be completed.
Next, a wet mount of the sample using potassium hydroxide (KOH) is a fast and inexpensive way of detecting fungi in the sample and eliminates the possibility of bacterial keratitis. The necessary diagnostic step is to isolate and grow cultures from the sample in Sabouraud dextrose agar (SDA), blood agar (BA) or chocolate agar (CA). SDA is considered the ideal culture medium for fungi growth but BA or CA are less expensive alternatives to SDA that also support fungi and bacterial growth. The complication in culturing to confirm diagnosis is the delay in early treatment and identification since culture growth may take any time between 72 hours to 2 weeks2. Accurate treatment based on the fungal organism is important since there is no standard treatment for all causes of fungal keratitis, but it requires time to obtain the information from these diagnostic tests. Prolonged identification adversely affects the effectiveness of the treatment, limiting the range of antifungal therapy and increasing the odds of recovery.
Recently, polymerase chain reaction (PCR) has been used as rapid and sensitive technique to identify the pathogens by extracting and amplifying small portions of DNA from the sample . PCR is a very time efficient but expensive method since it only takes 4-8 hours, in comparison to culturing the fungi that might take about 2 weeks.2 The advantage that PCR has over cultures is its ability to detect DNA samples from living and dead organisms unlike cultures, which only grow living organisms. The potential for false positives are higher however, since undetected contamination is possible during the process. PCR is an addition to using cultures for identification since each has its advantages and disadvantages that can be resolved using the other method.
Lastly, confocal microscopy can be used a noninvasive procedure for fungal keratitis diagnosis. This microscopy uses serial images to create 3D optical sections from the full cornea without physical harm2. These images allow for a rapid visualization of the current state of the cornea and possibly identify the microorganisms involved. Fungal filaments are large enough to be visible under the confocal microscope unlike bacteria. However, there are limitations to visualizing the pathogens despite the detailed view of the cornea.


Treatment and Prevention/ Prognosis

Treatment for fungal keratitis has been a challenge due to poor anti-fungal medications that cannot penetrate the cornea to get to the fungal organism1,7. Each medication has its benefits, limitations, and toxicity that affect the degree of treatment. Although it is possible to provide a combination of treatments, there are many factors to consider before using each agent, depending on the fungal pathogen. The antifungal agents used for treatment can be divided into three groups: polyenes (Amphotericin B, Natamycin), azoles (Miconazole, Fluconazole, Voriconazole), and allylamine and echinocandins (Caspofungin).1 These agents are usually applied topically via eye drops, taken orally, or injected. The only commercially available topical antifungal drug is 5% Natamycin that has been approved by the US Food and Drug Administration14. Natamycin works well against Candida, Aspergillus, and Fusarium but has poor penetrations into deeper layers of the eye, making it not as effective for severe infections. Amphotericin B can be administered via IV or eye drops (0.15%), but higher doses of IV are needed to ensure adequate amount of amphotericin B is applied. There is the risk of severe renal toxicity in administering high concentration of amphotericin B1. Voriconazole is suggested to be a better alternative to Natamycin since it has a wider range of activity and better penetration against filamentous fungi, namely Fusarium and Candidia. Voriconazole can be administered orally or via IV (0.05%-1%)1,2, . In certain parts of the world where keratitis is more common, Fluconazole and Miconazole are also options for treatment. Most topicals are given every hour initially for on average at least 3-4 weeks of treatment. In severe cases of fungal keratitis, surgical procedures such as penetrating keratoplasty (PK) and lamellar keratoplasty (LK) are treatment options to surgically remove the organism.2 PK uses a circular blade to excise lesions of the cornea and put a corneal graft in place, however there is a higher potential of graft rejection leading to a secondary infection that would make the situation worse. LK is more selective in only affecting the infected layers of the corneal surface while leaving the basement layers of the cornea intact. To prevent contracting fungal keratitis, it is advised to wear protective eyewear when working in a vegetative environment. With contact lens wear, one should be aware of the length of use and maintain sterile hygiene to prevent infection.


Current Research

Current research in fungal keratitis is in progress for discovering new treatments. Recently, a study has shown that a surgical procedure called excimer laser phototherapeutic keratectomy (PTK) is a valuable therapeutic alternative for treating fungal keratitis, especially when the fungus is lodged deep inside the corneal layers16. PTK uses an excimer laser to remove lesions in the anterior stroma in a less invasive way than PK and LK. PTK also allows precise control of the procedure making it easy to use and leaving a smooth surface for corneal re-epithelialization. Based on the study from 47 patients treated with PTK from January 2005 to September 2012, 34 of the 47 eyes treated with PTK showed improvement in visual acuity and fast recovery. PTK may work in conjunction with current medications to provide a suitable treatment for severe cases of fungal keratitis.

References

Al-Badriyeh, D., et al., Clinical utility of voriconazole eye drops in ophthalmic fungal keratitis. Clin Ophthalmol, 2010. 4: p. 391-405.

Ansari, Z., D. Miller, and A. Galor, Current Thoughts in Fungal Keratitis: Diagnosis and Treatment. Curr Fungal Infect Rep, 2013. 7(3): p. 209-218.

Neoh, C.F., et al., Clinical utility of caspofungin eye drops in fungal keratitis. Int J Antimicrob Agents, 2014. 44(2): p. 96-104.

Jurkunas, U., I. Behlau, and K. Colby, Fungal keratitis: changing pathogens and risk factors. Cornea, 2009. 28(6): p. 638-43.

Tuli, S.S., Fungal keratitis. Clin Ophthalmol, 2011. 5: p. 275-9.

Alfonso, E.C., et al., Fungal keratitis associated with non-therapeutic soft contact lenses. Am J Ophthalmol, 2006. 142(1): p. 154-5.

Jin, K.W., et al., A case of fungal keratitis and onychomycosis simultaneously infected by Trichophyton species. BMC Ophthalmol, 2014. 14: p. 90.

Nielsen, S.E., et al., Incidence and clinical characteristics of fungal keratitis in a Danish population from 2000 to 2013. Acta Ophthalmol, 2014.

Martin, R., et al., The Candida albicans-specific gene EED1 encodes a key regulator of hyphal extension. PLoS One, 2011. 6(4): p. e18394.

Leal Jr, S.M. and E. Pearlman, The role of cytokines and pathogen recognition molecules in fungal keratitis – Insights from human disease and animal models. Cytokine, 2012. 58(1): p. 107-111.

Krishnan, S., E.K. Manavathu, and P.H. Chandrasekar, Aspergillus flavus: an emerging non-fumigatus Aspergillus species of significance. Mycoses, 2009. 52(3): p. 206-222.

Kim, S.J., et al., Clinical experiences in fungal keratitis caused by Acremonium. Clin Ophthalmol, 2014. 8: p. 283-7.

Sudan, R. and Y.R. Sharma, Keratomycosis:Clinical diagnosis,Medical and Surgical Treatment. JK Science Jan Mar 2003. 5(1): p. 3-10.

Tananuvat, N., et al., Prospective comparison between conventional microbial work-up vs PCR in the diagnosis of fungal keratitis. Eye (Lond), 2012. 26(10): p. 1337-43.

Niki, M., et al., Ineffectiveness of intrastromal voriconazole for filamentous fungal keratitis. Clin Ophthalmol, 2014. 8: p. 1075-9.

Li, L.M., et al., Excimer laser phototherapeutic keratectomy for the treatment of clinically presumed fungal keratitis. J Ophthalmol, 2014. 2014: p. 963287.

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