Article

PDF
Access to the PDF text
Service d'aide à la décision clinique
Advertising


Free Article !

Journal Français d'Ophtalmologie
Volume 40, n° 9
pages e307-e313 (novembre 2017)
Doi : 10.1016/j.jfo.2017.08.001
Received : 24 April 2017 ;  accepted : 29 August 2017
Editor's choice

Fungal keratitis
 

T. Bourcier a, , A. Sauer a, A. Dory b, J. Denis c, M. Sabou c
a Ophthalmology, Nouvel Hôpital Civil, EA7290, FMTS, University Hospitals and University of Strasbourg, BP 426, 67091 Strasbourg, France 
b Pharmacy, Nouvel Hôpital Civil, FMTS, University Hospitals and University of Strasbourg, BP 426, 67091 Strasbourg, France 
c Parasitology – Mycology, Microbiology Technical Platform, Nouvel Hôpital Civil, FMTS, University Hospitals and University of Strasbourg, BP 426, 67091 Strasbourg, France 

Corresponding author. Ophthalmology Department, Nouvel Hôpital Civil, 1, place de l’Hôpital, BP 426, 67091 Strasbourg cedex, France.
Summary

Fungal keratitis, or keratomycoses, are corneal infections which must be considered in cases of corneal trauma, prior corneal surgery, chronic ocular surface disease, topical corticosteroids or contact lens wear. Filamentous fungi or yeasts may be involved. Presenting clinical features such as corneal infiltrates with feathery edges and/or raised surface, intact epithelium with deep stromal involvement, satellite lesions, endothelial plaques, lack of improvement with antibiotics and worsening with steroids are suggestive of fungal keratitis. Corneal scraping for laboratory examination is mandatory. Medical management with antifungal eye drops and systemic agents should be started as soon as possible. Surgical interventions are required in a significant number of cases to control the infection. The prognosis of fungal keratitis is worse than that of bacterial keratitis.

The full text of this article is available in PDF format.

Keywords : Abscess, Antifungals, Cornea, Filamentous, Fungus, Keratitis, Mycosis, Scraping, Yeast


Fungal keratitis, or keratomycoses, are corneal infections which must be considered in cases of corneal trauma, prior corneal surgery, chronic ocular surface disease, topical corticosteroids or contact lens wear. Filamentous fungi or yeasts may be involved. Presenting clinical features such as corneal infiltrates with feathery edges and/or raised surface, intact epithelium with deep stromal involvement, satellite lesions, endothelial plaques, lack of improvement with antibiotics and worsening with steroids are suggestive of fungal keratitis. Corneal scraping for laboratory examination is mandatory. Medical management with antifungal eye drops and systemic agents should be started as soon as possible. Surgical interventions are required in a significant number of cases to control the infection. The prognosis of fungal keratitis is worse than that of bacterial keratitis.

Organisms

Over 70 species of fungus have been identified in the setting of keratitis [1]. Fungi may be classified as filamentous fungi or yeasts (Table 1). A third group consisting of dimorphic fungi having both a filamentous phase and a yeast phase is responsible for deep tissue mycoses but rarely keratitis. Filamentous fungi are ubiquitous in the environment, present on plants, in soil, in water and in the air in the form of spores. Yeasts are also widely distributed in the environment (soil, water, objects, food), the digestive or genital tract, and skin.

Infections due to filamentous fungi occur primarily in tropical climates: southern United States, Mexico, Central America, South America, Africa, Middle East, China, India, southeast Asia [2, 3]. In these regions, fungal keratitis may represent up to 80% of infectious keratitis.

Yeast-related keratomycoses are, in the very large majority of cases, due to Candida or Cryptococcus . Local or systemic immunosuppression constitutes the primary risk factor. Yeasts represent approximately 30 to 52% of fungal keratitis observed in countries with temperate climates: Europe, northern United States, Australia [4, 5, 6, 7]. In these regions, fungal keratitis represents between 1 and 5% of infectious keratitis.

Pathogenesis

The occurrence of a fungal infection implies an alteration in one or more of the cornea's anti-infectious defense systems (epithelial barrier, tear film, blinking). The inflammatory response to the infection depends on fungal reproduction, mycotoxins, secreted proteolytic enzymes and fungal antigens [8]. Fungi may penetrate the stromal lamellae, attack Descemet's membrane, spread into the anterior chamber and provoke endophthalmitis. The formation of biofilm is an important factor in the pathogenesis, notably for filamentous fungi such as Fusarium [9]. Corticosteroids and other immunosuppressive agents facilitate the development of fungal infections by inhibiting transcription of pro-inflammatory cytokines and chemokines. They also decrease the anti-infectious activity of macrophages as well as the ability of neutrophils to adhere [10].

Risk factors

Filamentous fungal infections occur most commonly in healthy corneas in the context of contact lens wear (risk factor found in 25 to 40% of series of keratomycoses) [3, 4, 5, 11], followed by corneal surgery or corneal trauma with plant material. This may be an indoor or outdoor plant or other types of plant matter (tree branches, fruits, vegetables). Certain professions involving outdoor activities (farming, agriculture, landscaping) are thus particularly at risk, which explains the male preponderance of filamentous fungal infections. There are also seasonal variations, with cases being more frequent in spring and autumn, during the harvest season [2]. Corneal traumas by the fingers, nails, metallic foreign bodies, insects, cow tails and food products have also been reported.

Local or systemic immunosuppression constitutes the primary risk factor for yeast infections [12]. Candida and other yeasts are opportunistic fungi, which infect diseased ocular surfaces such as those of corneal grafts, atopic keratoconjunctivitis, severe keratitis sicca, stromal herpes, fibrosing conjunctivitis, neurotrophic keratitis or exposure keratopathy. Certain causes of systemic immunosuppression may be associated with keratomycoses: diabetes, HIV infection, cancer and medication-induced immunosuppression.

Rare cases of fungal keratitis (yeasts and filamentous fungi) have been reported after corneal refractive surgery: LASIK, keratotomies, intracorneal ring segments, corneal cross-linking, or cataract surgery [11].

Clinical diagnosis

One or several risk factors are generally present on the patient's history. Functional signs of keratitis are present and of variable intensity depending on the degree of inflammation. Decreased visual acuity is variable depending on the location of the corneal lesions (infiltrate, edema) with respect to the visual axis, anterior chamber reaction, the presence of secretions and/or tearing reflex.

Biomicroscopy should look for signs suggestive of an active corneal infection: lid edema, conjunctival injection, chemosis, peripheral ring infiltrate, epithelial defect, localized (abscess) or diffuse (keratitis) suppurative stromal infiltrate. The location, color, density, dimensions, shape, edge regularity and depth of the infiltrate should be noted, as well as the existence of areas of melting, necrosis, stromal thinning, peri-lesional edema, satellite infiltrates, neovascularization, endotheliitis, or an anterior chamber reaction (Tyndall effect, hypopyon, fibrin, endothelial plaque). Examination of the cornea adjacent to the infected zone, the contralateral cornea, the lids, conjunctiva, sclera, tear film, anterior chamber and vitreous allow identification of ocular surface disease and/or complications associated with the corneal infection. Corneal sensitivity should be tested if a neurotrophic keratitis is suspected. All of these signs should be recorded in a detailed diagram performed at the initial exam and repeated throughout the follow-up.

Certain signs suggest fungal keratitis (Figure 1) [13]:

grayish corneal epithelium with an ulcerated or infiltrated surface; the epithelium is sometimes intact, healed over the stromal infiltrate which extends deeper;
stromal infiltrate with irregular edges, showing little or no inflammation, which on high magnification may sometimes exhibit filamentous fungal hyphae, explaining the “fluffy” appearance of the edges of the infiltrate;
heaped infiltrate;
microinfiltrates “satellite lesions” disseminated throughout the cornea;
Wessely's immune ring;
pigment deposits on the deep aspect of an ulcer (pigmented filamentous fungi);
endothelial plaques, hypopyon.



Figure 1


Figure 1. 

Aspergillus keratitis. Risk factor: contact lens wear. Signs: intense conjunctival injection, irregular fuzzy edges of the infiltrate and presence of satellite lesions.

Zoom

The infection may sometimes take on the appearance of a microcrystalline keratopathy (Candida ). Identification of the infectious process is sometimes more difficult in cases of infection occurring secondary to corneal pathology or in the case of previous antibiotic treatment.

The time course of the infection depends upon the virulence of the fungus, the size of the inoculum and host resistance. Progression of fungal keratitis is generally slower than that of bacterial keratitis. The first signs appear several hours or days after the trauma or the wearing of infected contact lenses, but may sometimes appear even later. However, infections with Aspergillus or Fusarium may progress very rapidly to corneal perforation and endophthalmitis, notably when corticosteroids have been prescribed. Severe suppurative infections may also result from yeast infection.

Complications resulting from keratomycosis are numerous: stromal melt, descemetocele, corneal ectasia or perforation (5 to 6 times more frequent than with bacterial keratitis), scleritis, ocular hypertension or hypotony, endophthalmitis, infectious eyeball melt and orbital cellulitis have been described.

Imaging

In vivo confocal microscopy (IVCM) sometimes allows early detection of keratomycoses by visualizing within the cornea linear structures 3 to 10μm in diameter and 200 to 400μm in length, with branches corresponding to filamentous fungi (Figure 2). Yeasts are too small to be visualized. This examination allows differentiation between fungi and other microorganisms (notably amoebae) and monitoring of efficacy of antifungal treatments [14]. However, IVCM cannot distinguish between Fusarium and Aspergillus , and culture remains essential to determine the causative fungus [15].



Figure 2


Figure 2. 

In vivo confocal microscopy. Fusarium filaments. 300×magnification.

Zoom

OCT imaging of the cornea may aid in the evaluation of infectious keratitis by showing possible endothelial plaques, quantifying the volume of the stromal infiltrate and loss of corneal tissue.

Corneal and anterior segment photography is a practical alternative to hand-drawn diagrams and can be indispensible for following lesions.

Microbiologic diagnosis

The search for a definitive diagnosis is highly desirable if keratomycosis is suspected, given the prognostic and therapeutic implications associated with these pathogens. Corneal scraping is the standard method of obtaining a specimen. It is performed by the ophthalmologist at the slit lamp, or under an operating microscope in the case of an associated surgical procedure. In order to optimize the diagnostic yield, it is preferable to perform the procedure prior to any antifungal treatment. Powder-free gloves are mandatory. Fluorescein and anesthetic should be eliminated from the ocular surface by abundant irrigation with sterile saline. The culture kit is prepared by the nurse assisting the physician during the procedure. This kit includes all the tools necessary to perform a direct examination on slides as well as culture media and PCR. It thus allows for complete microbiologic examination including, according to the clinician's judgement, bacteriologic, mycologic, parasitologic, and if necessary, virologic studies. At first, a sterile stainless steel scalpel blade is used. It is important to selectively sample the base and edges of the ulcer without touching the patient's conjunctiva or lids. The sample from the scraping is spread onto a cytology slide. The slide is then placed in a transport container. After Gram staining, this slide is used for direct bacteriologic and mycologic examination. KOH, May-Grünwald Giemsa, calcofluor white, and lactophenol cotton blue stains may also be employed if a fungal infection is suspected (Figure 3) [1]. Two additional scrapings are performed with culturette swabs for bacterial and fungal culture [16]. A fungal culture medium containing antibiotics is inoculated in the mycology laboratory. Bacteriologic examination must be systematically performed, since there is a 30 to 40% rate of bacterial co-infection [7]. All of these corneal specimens, along with the requisition sheets and possibly the patient's contact lenses and cases, must be transported to the microbiology laboratory within 2 hours after scraping. The laboratory will then specifically isolate, by various complementary techniques (direct examination of the slides, cultures, molecular biology) the fungi and possible other pathogens responsible for the infection. The culture will become positive in 24 to 48 hours for yeast keratitis and 2 to 4 days on average for filamentous fungal keratitis, although certain fungi may require a longer incubation period (from 1 to 3 weeks), such as Fusarium . Morphologic analysis, proteomic and biochemical testing allows identification of the fungus in 24 hours to 7 days. A susceptibility profile may also be concurrently performed.



Figure 3


Figure 3. 

Corneal scraping, direct examination. Lactophenol cotton blue stain. Conidiophores and cylindrical conidia of Metarhizium anisopliae . 400×magnification.

Zoom

The flap must be lifted in the operating room to sample the interface in the case of post-LASIK corneal infection.

Culturing an infected corneal suture may be of value.

Anterior chamber paracentesis is contraindicated except in the case of associated endophthalmitis.

Corneal biopsy may be considered in the case of deep infection unresponsive to antibiotic treatment and undiagnosed by previous corneal scraping.

Microbiologic analysis is sometimes performed on the host corneal button, in the case of a tectonic graft.

Medical treatment

Topical anti-infectious medications are begun once the specimens have been taken. It is chosen empirically, considering the severity of the lesions, the initial clinical impression and the results of direct microbiologic examination. If the patient is not hospitalized, close ambulatory follow-up is required, including an ophthalmologic examination every 24 to 48hours. Table 2 lists the main antifungal agents currently available.

No antifungal eye drops are available in community pharmacies in France. With the exception of natamycin, the drops are compounded by hospital pharmacies from antifungal solutions or powders designed for systemic use. There is no international consensus on the agent or combination of agents to be used [17]. Table 3 combines the most frequent antifungal protocols in the literature.

Adjuvant therapy

Irrigation several times per day with saline may eliminate secretions and inflammatory mediators present on the ocular surface.

Regular debridement of the infiltrate, daily at first, then twice per week, decreases the infectious load, removes necrotic material and increases the efficacy of antifungals.

Daily washing of the face with soap as well as the hands with a water-alcohol solution is necessary prior to instillation of the drops.

Discontinuation of contact lens wear.

Discontinuation of topical corticosteroids.

Cessation of tobacco, which slows corneal healing [18].

Simultaneous or deferred treatment of chronic ocular surface disease.

Management of associated systemic immunosuppression.

Other eye drops may be administered if necessary: cycloplegic drops for pain relief (in the absence of contraindications, combined with oral analgesics) and for prevention of synechiae, glaucoma drops in the case of ocular hypertension.

Patient education regarding the causative risk factor and anatomic and visual prognosis of the infection.

Patient education regarding compliance in treating the current infection and methods of preventing a recurrence.

Psychological support if necessary.

Surgical treatment

Combined with keratectomy or debridement of the corneal ulcer, an amniotic membrane graft may prove useful by promoting the process of corneal healing [19]. An analgesic and anti-inflammatory effect of the amniotic membrane has also been demonstrated.

Phototherapeutic keratectomy by excimer laser has been proposed for infections localized to the anterior stroma [20].

Tectonic corneal transplantation is necessary when the integrity of the globe is threatened: severe, progressive infection despite medical treatment, overt or imminent corneal perforation. (Deep) anterior lamellar or penetrating keratoplasty may be employed. However, the prognosis of keratoplasties performed on an infected eye is poor (risk of infectious recurrence, increased risk of rejection), and to the extent possible, a wait of at least 12 months after resolution of the infectious episode is advisable prior to performing a keratoplasty for optical reasons. Associated procedures (cataract surgery, glaucoma surgery, posterior vitrectomy) and multiple grafts are sometimes necessary [21].

Amputation of an infected, necrotic LASIK flap is sometimes necessary.

In the case of a small diameter perforation, cyanoacrylate glue or a small button graft may be considered.

Several cases of infectious stromal melts resistant to anti-infectious treatment have been treated by corneal cross-linking. This procedure is still being evaluated for fungal keratitis [22, 23].

Conjunctival flap, retrobulbar injection of xylocaine/chlorpromazine and evisceration or enucleation are indicated in the most severe cases.

Prognosis

The prognosis of fungal keratitis is worse than that of bacterial keratitis. The course is favorable with medical treatment in 50–70% of cases [21]. A corneal graft, tectonic or delayed, is necessary in 30 to 54% of cases [6, 7, 21, 24, 25]. These infections may lead to loss of the globe in 10 to 25% of cases. However, these figures vary greatly as a function of the centers and countries, and depend on severity criteria present upon initial management of the infection.

Factors favoring a worse prognosis include: a delay in diagnosis>2 weeks [26], increased patient age, size of the stromal infiltrate, size of the epithelial defect [27], pigmentation of the ulcer, presence of satellite lesions, anterior chamber involvement, scleritis, amount of visual loss at initial management, non-response to initial antifungal treatment [28], high MIC's [24], Aspergillus infection [29], and fungal/bacterial co-infection [30, 31].

Disclosure of interest

The authors declare that they have no competing interest.


 See this article unabridged, illustrated and detailed, with electronic enhancements in EMC – Ophtalmologie : Bourcier T, Sauer A, Dory A, Denis J. Kératites fongiques. EMC – Ophtalmologie 2017 [Article 21-200-D-27].

References

Thomas P.A., Kaliamurthy J. Mycotic keratitis: epidemiology, diagnosis and management Clin Microbiol Infect 2013 ;  19 : 210-220 [cross-ref]
Ghosh A.K., Gupta A., Rudramurthy S.M., Paul S., Hallur V.K., Chakrabarti A. Fungal keratitis in North India: spectrum of agents, risk factors and treatment Mycopathologia 2016 ;  181 : 843-850 [cross-ref]
Ansari Z., Miller D., Galor A. Current thoughts in fungal keratitis: diagnosis and treatment Curr Fungal Inf Rep 2013 ;  7 : 209-218 [cross-ref]
Gower E.W., Keay L.J., Oechsler R.A., and al. Trends in fungal keratitis in the United States, 2001 to 2007 Ophthalmology 2010 ;  117 : 2263-2267 [cross-ref]
Gaujoux T., Borsali E., Goldschmidt P., and al. Fungal keratitis in France Acta Ophthalmol 2011 ;  89 : e215-e216
Nielsen S.E., Nielsen E., Julian H.O., and al. Incidence and clinical characteristics of fungal keratitis in a Danish population from 2000 to 2013 Acta Ophthalmol 2015 ;  93 : 54-58 [cross-ref]
Ho J.W., Fernandez M.M., Rebong R.A., Carlson A.N., Kim T., Afshari N.A. Microbiological profiles of fungal keratitis: a 10-year study at a tertiary referral center J Ophthalmic Inflam Infection 2016 ;  6 : 5 [cross-ref]
Karthikeyan R.S., Leal S.M., Prajna N.V., and al. Expression of innate and adaptive immune mediators in human corneal tissue infected with Aspergillus or Fusarium J Infect Dis 2011 ;  204 : 942-950 [cross-ref]
Mukherjee P.K., Chandra J., Yu C., Sun Y., Pearlman E., Ghannoum M.A. Characterization of Fusarium keratitis outbreak isolates: contribution of biofilms to antimicrobial resistance and pathogenesis Invest Ophthalmol Vis Sci 2012 ;  53 : 4450-4457 [cross-ref]
Sauer A., Abry F., Lhermitte B., Candolfi E., Speeg-Schatz C., Bourcier T. [Purulent corneal melting secondary to multidrug-resistant Fusarium oxysporum aggravated by topical corticosteroid therapy] J Fr Ophthalmol 2008 ;  31 : 534[e1–5].  [inter-ref]
Yildiz E.H., Abdalla Y.F., Elsahn A.F., and al. Update on fungal keratitis from 1999 to 2008 Cornea 2010 ;  29 : 1406-1411 [cross-ref]
Ong H.S., Fung S.S., Macleod D., Dart J.K., Tuft S.J., Burton M.J. Altered patterns of fungal keratitis at a London ophthalmic referral hospital: an eight-year retrospective observational study Am J Ophthalmol 2016 ;  168 : 227-236 [inter-ref]
Leck A., Burton M. Distinguishing fungal and bacterial keratitis on clinical signs Community Eye Health 2015 ;  28 : 6-7
Labbe A., Khammari C., Dupas B., and al. Contribution of in vivo confocal microscopy to the diagnosis and management of infectious keratitis Ocular Surf 2009 ;  7 : 41-52 [cross-ref]
Chidambaram J.D., Prajna N.V., Larke N., and al. In vivo confocal microscopy appearance of Fusarium and Aspergillus species in fungal keratitis Br J Ophthalmol 2017 ;  101 : 1119-112310.1136/bjophthalmol-2016-309656 [cross-ref]
Pakzad-Vaezi K., Levasseur S.D., Schendel S., and al. The corneal ulcer one-touch study: a simplified microbiological specimen collection method Am J Ophthalmol 2015 ;  159 : 37-43[e1].  [inter-ref]
FlorCruz N.V., Evans J.R. Medical interventions for fungal keratitis Cochrane Database Syst Rev 2015 ; CD004241
Jetton J.A., Ding K., Kim Y., Stone D.U. Effects of tobacco smoking on human corneal wound healing Cornea 2014 ;  33 : 453-456 [cross-ref]
Zeng B., Wang P., Xu L.J., Li X.Y., Zhang H., Li G.G. Amniotic membrane covering promotes healing of cornea epithelium and improves visual acuity after debridement for fungal keratitis Int J Ophthalmol 2014 ;  7 : 785-789
Li L.M., Zhao L.Q., Qu L.H., Li P. Excimer laser phototherapeutic keratectomy for the treatment of clinically presumed fungal keratitis J Ophtalmol 2014 ;  2014 : 963287
Rogers G.M., Goins K.M., Sutphin J.E., Kitzmann A.S., Wagoner M.D. Outcomes of treatment of fungal keratitis at the University of Iowa Hospitals and Clinics: a 10-year retrospective analysis Cornea 2013 ;  32 : 1131-1136 [cross-ref]
Papaioannou L., Miligkos M., Papathanassiou M. Corneal collagen cross-linking for infectious keratitis: a systematic review and meta-analysis Cornea 2016 ;  35 : 62-71 [cross-ref]
Uddaraju M., Mascarenhas J., Das M.R., and al. Corneal cross-linking as an adjuvant therapy in the management of recalcitrant deep stromal fungal keratitis: a randomized trial Am J Ophthalmol 2015 ;  160 : 131-134[e5].  [inter-ref]
Oechsler R.A., Yamanaka T.M., Bispo P.J., and al. Fusarium keratitis in Brazil: genotyping, in vitro susceptibilities, and clinical outcomes Clin Ophthalmol 2013 ;  7 : 1693-1701 [cross-ref]
Ramakrishnan T., Constantinou M., Jhanji V., Vajpayee R.B. Factors affecting treatment outcomes with voriconazole in cases with fungal keratitis Cornea 2013 ;  32 : 445-449 [cross-ref]
Keay L.J., Gower E.W., Iovieno A., and al. Clinical and microbiological characteristics of fungal keratitis in the United States, 2001–2007: a multicenter study Ophthalmology 2011 ;  118 : 920-926 [cross-ref]
Prajna N.V., Krishnan T., Mascarenhas J., and al. Predictors of outcome in fungal keratitis Eye 2012 ;  26 : 1226-1231
Sun C.Q., Prajna N.V., Krishnan T., and al. Effect of pretreatment with antifungal agents on clinical outcomes in fungal keratitis Clin Exp Ophthalmol 2016 ;  44 : 763-767 [cross-ref]
Wang L., Wang L., Han L., Yin W. Study of pathogens of fungal keratitis and the sensitivity of pathogenic fungi to therapeutic agents with the disk diffusion method Curr Eye Res 2015 ;  40 : 1095-1101 [cross-ref]
Fernandes M., Vira D., Dey M., Tanzin T., Kumar N., Sharma S. Comparison between polymicrobial and fungal keratitis: clinical features, risk factors, and outcome Am J Ophthalmol 2015 ;  160 : 873-881[e2].  [inter-ref]
Bourcier T., Sauer A., Dory A., Denis J., Sabou M. Kératites fongiques EMC Ophtalmologie 1 2017 ; 10.1016/S0246-0343(17)78702-3[Article 21-200-D-27].

Further reading

See this article, unabridged, illustrated and detailed, with electronic enhancements, in EMC – Ophtalmologie : Bourcier T, Sauer A, Dory A, Denis J. Kératites fongiques. EMC – Ophtalmologie 1 2017 [Article 21-200-D-27], doi:10.1016/S0246-0343(17)78702-3.



© 2017  Elsevier Masson SAS. All Rights Reserved.
EM-CONSULTE.COM is registrered at the CNIL, déclaration n° 1286925.
As per the Law relating to information storage and personal integrity, you have the right to oppose (art 26 of that law), access (art 34 of that law) and rectify (art 36 of that law) your personal data. You may thus request that your data, should it be inaccurate, incomplete, unclear, outdated, not be used or stored, be corrected, clarified, updated or deleted.
Personal information regarding our website's visitors, including their identity, is confidential.
The owners of this website hereby guarantee to respect the legal confidentiality conditions, applicable in France, and not to disclose this data to third parties.
Close
Article Outline