|
 
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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 23
| Issue : 1 | Page : 1-8 |
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Fungal infections of the eye
Savitri Sharma
Jhaveri Microbiology Centre, L. V. Prasad Eye Institute, Hyderabad, Telangana, India
| Date of Submission | 14-Jun-2021 |
| Date of Acceptance | 25-Jul-2021 |
| Date of Web Publication | 16-Sep-2021 |
Correspondence Address:
Dr. Savitri Sharma
Jhaveri Microbiology Centre, L. V. Prasad Eye Institute, Road no. 2, Banjara Hills, Hyderabad - 500 034, Telangana
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/jacm.jacm_53_21
Fungi are living organisms that are useful in the nature for cellulose degradation and decay of organic matter. They are useful for antibiotic synthesis and food maturation. At the same time there are several species that are pathogenic to man, animals and plants. They can cause infections in ocular tissues such as cornea, sclera, choroides, retina and vitreous. Fortunately, fungal infections are not frequent and are basically opportunistic infections. The exogenous infection is more common in tropical and subtropical parts of the world owing to their abundance in the environment as saprophytes. Prolonged treatment with corticosteroids or broad spectrum antibiotics, diabetes, acquired immunodeficiency syndrome, organ transplantation, malignancy and immunodeficiency conditions are some of the risk factors that may contribute to fungal infections. This review article is confined to ocular fungal infections, their pathogenesis, epidemiology, clinical features and laboratory diagnosis in brief. By far, fungal infections are easier to diagnose than treat. Availability of antifungal drugs is limited and a majority of them have serious side effects. Antifungal susceptibility testing is not common and data related to the development of resistance are meagre. Ophthalmic preparations for the treatment of fungal infections of the eye are very few and off label use of systemic antifungals as topical drugs is common. The science of fungal ocular infections is still evolving, with increasing data coming from just a few countries.
Keywords: Blepharitis, culture, dacryocystitis, direct microscopy, endophthalmitis, eye, fungal infection, keratitis, laboratory diagnosis, polymerase chain reaction, rhino-orbito-cerebral mucormycosis, scleritis, sequencing
How to cite this article:
Sharma S. Fungal infections of the eye. J Acad Clin Microbiol 2021;23:1-8 |
| Introduction | |  |
As in other external surfaces of the body, the external surface of the eye consisting of the lids, adnexa and conjunctiva harbour a commensal microbial flora while the inner portions of the eye are free of organisms. Some of the commensals are more common and constitute the resident flora such as Staphylococcus species, most common being Staphylococcus epidermidis, Propionibacterium acnes and Corynebacterium species. However, any environmental microorganism including fungus can form a transient flora in the external surface of the eye. Several natural factors such as blinking reflex of the lids, triple-layered tear film and antimicrobial action of the tear fluid containing IgA, lysozyme and lactoferrin protect the eye. Nevertheless, all parts of the eye are susceptible to either endogenous or exogenous infection influenced by various predisposing factors. The infection may be caused by microorganisms of all classes including fungi.
Exogenous infection is facilitated by break in superficial epithelium due to trauma, contact lens wear or other causes, whereas endogenous infections are usually blood borne that may affect the posterior segment of the eye. Local immunity and health of the external surface of the eye as well as systemic immunity play significant roles in the pathogenesis of an infection. The first case of fungal panophthalmitis was reported in 1913 as cited by Vanzzini Zago et al.[1] Three cases of keratitis in patients from Africa with invasion of the fungal infection to corneal epithelium, stroma, endothelium and reaching vitreous were described in 1958.[2] Diagnosis of both intraocular and extraocular infections is achieved on the basis of clinical features aided by microbiological investigations. Conventional microbiological techniques are currently being complemented by molecular techniques for diagnosis. This review is limited to pathogenesis, clinical features and laboratory diagnosis of fungal infections of the eye.
| Pathogenesis of Fungal Infections | | |
External surface of the eye with its bacterial flora and natural protective factors is usually not amenable to fungal infection. While conventional microbiological methods generally do not show fungal resident flora of the anterior surface of the eye in culture, advanced next generation sequencing methods have shown the presence of genomes of fungal species.[3] Systemic or topical corticosteroids or antibiotics administration may lead to alteration in normal flora and allow colonization and growth of fungi in the anterior part of the eye. Of all fungal eye infections, the most common is the corneal infection known as keratomycosis or mycotic keratitis. Trauma to the cornea leading to breach of corneal epithelium is a predisposing factor for this condition. Surgical procedures such as cataract surgery, keratoplasty and radial keratotomy are additional risk factors that may introduce fungi into the eye. Endophthalmitis may be associated with intraocular lens (IOL) implantation and contaminated irrigating solutions.[4] Elsewhere in the body, polysaccharide in fungal cell wall is known to activate complement and IgA, providing protection against fungal infections, however, it is not known whether this phenomenon plays a role in the eye. Clinical studies and clinical experience[5] have shown worsening of fungal infection with topical and systemic corticosteroids which suggests role of immunity (local and systemic) in protection of the eye from fungal infections. In addition, ocular fungal infection is often associated with systemic immunosuppression such as patients with human immunodeficiency virus infection, or transplantation or cancer therapy. Chemotherapy induced neutropenia may lead to fungal infection of inner parts of the eye such as retina and choroid through blood stream. Fungal infection without leucopenia may occasionally result with inoculation of high dose of fungi.[6],[7] Cell-mediated immunity (CMI) seems to play a role in protection against fungal infections which is exemplified by Cryptococcus neoformans infection of the orbit or chorioretina in patients with CMI deficiency. The host response to fungal infection of the cornea is characterised by acute suppurative inflammation or chronic inflammation or granulomatous inflammation. Several enzymes such as proteases and phospholipases as well as mycotoxins have been reported to be elaborated by the fungi that are responsible for their pathogenicity.
| Fungal Infections of the Orbit, Lids and Lacrimal System | | |
In medically immunosupressed patients with organ transplantation or HIV infection, rhino-orbital-cerebral mucormycosis is often caused by Mucorales such as Mucor, Absidia, Rhizomucor, Cunnighamella and Rhizopus that are zygospore forming moulds. In the recent pandemic of COVID-19, the incidence of these infections have gone up many fold owing to multiple factors including diabetes, corticosteroid administration in the treatment of COVID-19 and immunomodulatory effect of severe acute respiratory syndrome coronavirus 2 virus.[8] The terms mucormycosis or zygomycosis are used to refer to the subcutaneous or deep infections such as rhino-orbital, rhino-cerebral, cerebral, gastrointestinal and pulmonary mycoses caused by any one of these moulds. The term aspergillosis is used for pulmonary, paranasal, sinusal or rhino-orbital fungal infrequent infection caused by diverse species of Aspergillus.[9] Although rare, invasive sino-orbital fungal infection can also occur in immunocompetent hosts.[10] Several species of fungi including Aspergillus, Mucor and Rhizopus may be involved. In one report, patients with orbital aspergillosis in immunocompetent individuals were infected with Aspergillus flavus in 86% and Aspergillus fumigatus in the remaining.[11] The most common presentation reported is proptosis followed by diplopia.[12] The disease seems to affect young individuals, however, some studies have reported older age as a predisposing risk factor. Computed tomography is the most common imaging method that is recommended in patients suspected to have sino-orbital disease. Blood cultures are usually negative. Biopsy from the lesion may show broad, sparsely septate or aseptate branching filaments with ribbon-like folds [Figure 1] if a Mucorale (Mucor, Rhizopus, Apophysomyces, etc.,) is involved. These filaments are easily seen on hematoxylin and eosin stained sections that spread along nerves and invade into blood vessels. Aspergillus filaments are usually thin, septate and branch at acute angles. In addition to haematoxyline and eosin, histopathology stains should include Gomori's methenamine silver and periodic acid–Schiff. It is not clear whether fine-needle aspiration biopsy would be useful in the diagnosis of orbital fungal infections; however, it can be tried in patients with sino-orbital mass involving the posterior orbit in the face of negative paranasal sinus biopsy and difficult incisional biopsy.[13] Specific antibodies to Aspergillus have been used for immunohistochemistry to identify Aspergillus species.[14] Detection of serum Galactomannan and β-D glucan tests for the diagnosis of invasive fungal infections is not of much value.[15] Fungal filaments can be demonstrated in direct examination of the sample (Gram stain, potassium hydroxide with or without calcofluor white stain). The organisms can be grown easily on ordinary media such as blood agar and Sabouraud dextrose agar (SDA) and identified by their colony characteristics and spores. Identification is also aided by DNA sequencing of the ITS region of the 18S rRNA gene of fungus.[16] Polymerase chain reaction (PCR) can be done with DNA extracted from the paraffin sections as well.[17],[18],[19] | Figure 1: Aseptate, broad, thin walled, branching filaments with ribbon-like folds suggestive of Mucorales in orbital biopsy of a patient with post COVID-19 rhino-orbital mucormycosis (potassium hydroxide with calcofluor white stain, ×400)
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Fungi may cause periorbital necrotising fasciitis. One case in a healthy young adult caused by Cryptococcus has been reported wherein there was a definite history of preceding trauma with a wooden splinter.[20] A large series has been reported from India in immunocompetent patients with precedent trauma.[21] In this series, five were Apophysomyces species and two had co-infection with Aspergillus and Candida species. Necrotising fasciitis is a medical emergency requiring heavy doses of antibiotics. Surgical debridement may be indicated to prevent spread.
Fungal infections of the eyelids, fungal blepharitis, are less common compared to other fungal ocular infections. They may be caused by dermatophytes, which are mainly skin pathogens.[22] Clinically, they may mimic allergic skin reaction, oedema, ulceration, skin desquamation and loss of eyelashes.
Canaliculitis of fungal aetiology is rare but may be caused by Candida species and is characterised by chronic course of the disease. Older women with chronic conjunctivitis and inflammatory disorders of ocular adnexa resistant to antibiotics are more likely to develop fungal canaliculitis. The treatment is surgical dissection of lacrimal canaliculi, removal of their content with subsequent instillations and washing of tear ducts with antiseptics and antifungal drugs. Relapses are common.[23]
Fungal dacryocystitis, reportedly caused by Candida albicans is uncommon, and may be implicated in nasolacrimal duct obstruction.[24] Its association with dacryoliths is known, however, it is not known whether it is a cause or the effect. The possibility of a fungal infection should be considered in chronic dacryocystitis, particularly in the presence of corneal ulceration or endophthalmitis.[24] A case of bilateral chronic fungal dacryocystitis caused by Candida dublinensis has been described in a HIV negative woman.[25] An unusual case of Sporothrix schenckii was reported in 2018 from China in a 34-year old woman who presented with a nodular lesion in the medial angle of the eye.[26]
| Fungal Infections of Conjunctiva, Cornea and Sclera | | |
Fungal infection of the conjunctiva is very rare. Conjunctivitis caused by Candida species has been described in the newborns and school children[27] and in adults[28] with the primary infection localised in oral mucosa or vagina. A follicular-papillary chronic conjunctivitis with no response to antibiotic and a slow progress points to Candida conjunctivitis. The patients often have a slow response and in some patients, conjunctival membranes or pseudomembranes may be observed. One case of fungal conjunctivitis caused by dimorphic fungus Sporothrix schenckii was reported in Japan with the diagnosis made by histological study. The patient responded to topical fluconazole and oral potassium-iodine.[29] A very rare conjunctival fungal infection reported by Bittencourt et al.[30] was caused by Conidiobulus coronatus that began in the conjunctiva following injury that was contaminated with soil.
Fungal keratitis is a common infection of the eye seen in India. Fungi gain access into the corneal stroma through an epithelial defect which may be due to external trauma, a compromised ocular surface, or previous surgery. The fungal organisms can penetrate deep into the stroma and reach the anterior chamber through the Descemet's membrane. It is believed that once the organisms gain access into the anterior chamber or to the iris and lens, eradication of the organism becomes extremely difficult. The prevalence of fungal keratitis is high in tropical regions of the world including India.[31] A wide variety of species have been reported from different parts of the world [Table 1]. Earlier considered protozoa, Microsporidia are classified under fungi. They are associated with keratoconjunctivitis and stromal keratitis.[32] Clinically, it is difficult to diagnose microsporidial stromal keratitis and laboratory diagnosis is required to make the diagnosis. In the absence of availability of specific treatment, many of the cases end up with penetrating keratoplasty. Intraocular invasion of the microsporidia in a case of stromal keratitis has been reported.[33] Clinically similar to fungal keratitis, Pythium insidiosum keratitis is increasingly being reported from India.[34],[35] Pythium insidiosum is an oomycete that belongs to the kingdom Stramenipila. Reported mostly from South East Asia, it causes vascular, systemic, cutaneous and ocular forms of infection in humans and subcutaneous and gastrointestinal forms of infection in animals. The systemic infections can be fatal. The infection occurs through the direct contact of wounds with Pythium insidiosum zoospores contaminated water. Although the disease is rare, the incidence of Pythium insidiosum keratitis is 5.5% of all fungal keratitis in an eye hospital-based study in India.[34] The morphological features of the organism in tissues resembles fungal filaments of zygomycetes in being broad, aseptate with ribbon-like folds [Figure 2]. The identification of the organism in patients with keratitis is important to institute specific treatment. In vitro formation of zoospores is a reliable method. Unlike fungi, the cell membrane of Pythium insidiosum lacks ergosterol and therefore is resistant to antifungal therapy. Antibacterial antibiotics such as linezolid and azithromycin have been shown to be useful in treatment.[35] | Table 1: Fungal species reported from corneal scraping of patients with fungal keratitis
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 | Figure 2: Aseptate, broad, branching filaments with ribbon-like folds suggestive of Pythium species in corneal scraping of a patient with microbial keratitis (potassium hydroxide with calcofluor white stain, ×400)
Click here to view |
Fungi are a common cause of scleritis in tropical countries like India.[36] The prevalence of fungal scleritis varies between 3% and 38% in different studies.[36],[37] Fungal scleritis is commonly reported with Aspergillus, other fungi include Paecilomyces lilacinus, Scedosporium, Cephalosporium, Penicillium, Cladosporium, Candida parapsilosis, Fusarium, Rhizopus, Acremonium, Colletotrichum dematium, Histoplasma capsulatum and Aspergillus terreus.[36],[38],[39],[40] The treatment of fungal scleritis is challenging due to the difficulty in diagnosis, the difficulty of drug penetration due to avascular nature of sclera and the limited number of antifungal agents available in the market. Existing literature does not provide any consensus on the class of antifungal or the route of administration to be followed. Surgical debridement is needed to debulk the infected stromal layers and promote penetration of antifungal agents. Outcome in fungal scleritis is generally poor.[36],[38],[41]
| Fungal Infections of the Uvea, Retina and Vitreous | | |
Any inflammation involving the uveal tract is termed uveitis. Chronic uveitis can be granulomatous or nongranulomatous. The infection may be exogenous or endogenous from a contiguous structure (sinuses, orbital abscess and cellulitis) or haematogenous. Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans and Aspergillus fumigatus are some of the fungi associated with choroiditis and chorioretinitis. Candida albicans may be associated with endogenous endophthalmitis, the risk factors for which include prior antibiotic therapy, prior surgery, diabetes mellitus and alcoholism. Vitreous culture is usually positive for Candida albicans and the organism may be grown from the blood. Cryptococcus neoformans has a predilection for the central nervous system and intraocular involvement may occur as either haematogenous spread or direct extension from the central nervous system infection. As is well known, this budding yeast is identified by its capsule, inability to form pseudohyphae and urease production. Like Candida, it grows well in media such as blood agar and SDA. Choroiditis and retinitis due to Aspergillus fumigatus is generally haematogenous in origin and occurs mostly in immunocompromised patients. It may also cause acute bilateral necrotising retinitis.[42]
Fungal endophthalmitis is either exogenous (trauma, surgery) or endogenous (transient fungemia in systemic disease). Contaminated intravenous infusions have been reported from India to be associated with endogenous endophthalmitis.[43] An overview of fungal endophthalmitis has been published recently from India that includes 723 patients from 7 large referral eye care centres.[44] The study listed Aspergillus, Fusarium and Candida as the most common genera involved. Candida species. is often reported as a cause of endogenous endophthalmitis in immunocompromised patients with renal transplantation or acquired immunodeficiency syndrome. The first case of endogenous endophthalmitis caused by Apophysomyces elegans-a Mucorale, was reported in 2014. The patient was not immunocompromised but had a history of soil contaminated trauma some time ago.[45] A rare case of endogenous endophthalmitis with subretinal abscess caused by Cryptococcus neoformans was reported in an HIV-infected patient who had discontinued anti-retroviral therapy.[46] Delayed postcataract surgery endophthalmitis caused by Stephanoscus ciferrii was reported wherein the organism was sequestered in the capsular bag with IOL. The patient required IOL explanation for complete removal of the infection.[47] There are reports of fungal endogenous endophthalmitis (Candida albicans, Aspergillus flavus) in COVID-19 recovered patients. Steroid therapy resulting in lowered immunity is believed to be the predisposing factor.[48] Whatever the basis of infection, endophthalmitis is a potentially blinding disease with irreversible rapid tissue damage; therefore, early diagnosis and prompt treatment are central to successful management.
| Laboratory Diagnosis of Ocular Infections | | |
An early clinical and laboratory diagnosis is very important for specific therapy and consequent better visual prognosis. As is true for any infection, the clinical samples for the diagnosis of eye infections must be collected from the site of infection. Important aspects in sample collection include; (a) to be collected carefully without causing much pain and discomfort to the patient, (b) must be collected from the site of lesion ensuring minimum loss during collection, (c) direct processing without resorting to transport media, (d) avoid delay in processing and (e) prolonged incubation (1–2 weeks) of most media to allow growth of slow growing/fastidious organisms. Types of clinical samples that may be collected for the diagnosis of various eye infections are shown in [Table 2]. | Table 2: Samples to be collected from patients with fungal eye infections
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Processing of clinical samples
As mentioned before, in most cases, no transport medium is recommended for submitting ocular samples to the laboratory for microbiological investigation. In case of non-availability of the microbiology laboratory in the premises of the hospital, the required slides and media may be obtained beforehand and kept in reserve for use. The prepared slides/inoculated media may be transported in secure boxes to the laboratory at the earliest. Items such as contact lens cases and contact lens solutions may be directly submitted to the laboratory for processing. The direct smear examination methods and common culture media used for isolation of bacteria and fungi need to be included even if the clinical diagnosis may be fungal. The common staining methods for the microscopic observation of the smears made from clinical samples include Gram stain and potassium hydroxide with calcofluor white stain (KOH + CFW). The latter method requires a fluorescence microscope, in the absence of which 10% KOH can be used. Samples such as corneal buttons/biopsies, eviscerated contents or any other tissues should be submitted for histopathological study. Smears are generally not made from samples such as contact lenses, IOL and corneal biopsy/buttons. These samples are aseptically cut into pieces or minced and placed for culture of bacteria and fungi in appropriate media. Most samples for PCR; except vitreous, anterior chamber fluid or pus; are placed in sterile phosphate-buffered saline pH 7.2 and submitted to the laboratory where they may be retained at −20°C until tested. PCR can identify the offending organisms in <24 h. It is considered useful in the diagnosis of bacterial as well as fungal endophthalmitis since the sensitivity of conventional culture methods is low.
Corneal scraping stained with Gram stain showing septate fungal filaments is shown in [Figure 3]. The types of media used for culture generally include common laboratory media such as blood agar, chocolate agar, brain heart infusion broth, thioglycollate broth, SDA, potato dextrose agar (PDA). All media are incubated at 37°C except SDA and PDA, which require 25°C–27°C (BOD incubator). SDA and PDA may be added with gentamicin or chloramphenicol (to prevent bacterial growth) but not cycloheximide (inhibits growth of saprophytic fungi) as saprophytic fungi are the common pathogens in eye infections. Although most fungi associated with eye infections are saprophytes and grow within a week they may require incubation for 2–3 weeks for proper sporulation and identification. Size, colour, texture, consistency and number of colonies on the inoculation marks are counted and recorded. The growth of bacteria or fungus in culture is considered significant if the growth is confluent (more than 10 colonies) on the site of inoculation on solid media [Figure 4], or the organism was seen in the smears, or if the same organism is grown in more than one medium. | Figure 3: Septate, thin, fungal filaments seen in corneal scraping of a patient with microbial keratitis (Gram stain, ×1000)
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 | Figure 4: Chocolate agar and Saboraud dextrose agar incoulated with corneal scrapings of a patient with microbial keratitis showing yellowish green granular surface of a off white velvety fungal colony after two days of incubation at 27°C. The growth is suggestive of Aspergillus flavus
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Standard microbiological procedures are followed to establish the genus and species of the bacterial or fungal isolates. Conventional biochemical tests are now being replaced with modern automated systems such as Vitek 2 compact system, matrix-assisted laser desorption ionisation-time of flight mass spectrometry (MALDI-ToF-MS) for the identification of bacteria and yeast. However, a combination of conventional and automated methods are often required. Filamentous fungi continue to be identified on the basis of colony character and microscopic features. Several websites such as 'doctor fungus', “mycology online' and 'Atlas of clinical fungi' help in morphological identification, apart from standard text books. DNA sequencing of conserved genes in the identification of organisms is being increasingly adopted. For susceptibility testing of fungal isolates to antifungal drugs, CLSI-based micro broth dilution method is used.
Molecular techniques such as PCR are being increasingly used for the diagnosis of fungal infection, especially intraocular infections, since the load of fugal elements are low in these fluids. Negative microscopy and culture results in the presence of clinical disease are often challenging to the microbiologist and treating ophthalmologist. PCR is highly sensitive and may detect DNA of non-viable organisms, a fact that needs to be considered while interpreting the results. Samples from patients treated with antibiotics can also be used for the detection of DNA of the organism in the sample. Primers are designed to either help detect a particular organism or a group of organisms. Primers specific for a targeted organism have an overall limited value, however, are useful when a clinical feature points at specific organism for example mucormycosis. Several studies have reported application of panfungal PCR in the diagnosis of infectious endophthalmitis and keratitis. Primers based on 18S rDNA, ITS or 28S rDNA genes have been used.[49],[50],[51] These PCR tests are reported to be highly specific and sensitive to the detection level of 1 fg of fungal DNA. In one study, ITS gene-based PCR compared to culture showed increased detection of fungal endophthalmitis in 28.6% cases.[49] A recent study reported differentiation of fungus from Pythium insidiosum in a single PCR reaction.[52] For species identification by DNA sequencing a second step is required following panfungal PCR. Sequence of the amplified DNA is compared with similar sequences in databases using BLASTn program of the National Centre for Biotechnology Information (NCBI, GenBank database). A score of 97% and similarity of 98% allows the genus recognition and a score of 99% or more may assign a species name. Phylogenetic analysis further confirms the species in relation to known sequences available in the database. It allows comparison with type strains available. Using DNA sequencing and phylogenetic analysis, Pythium insidiosum has been established as a cause of keratitis that resembles fungal keratitis.[34]
In conclusion, fungal infections of the eye are common in tropical and subtropical regions of the world including India. The disease may or may not be associated with lowered immunity in the host. Trauma is a common predisposing factor. Both the ophthalmologists and microbiologists need to be cognizant of the clinical features, diagnostic methods and the antifungal drugs available. Appropriate sampling and processing are crucial to achieve supportive laboratory findings.
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Conflicts of interest
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]
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