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Ghenciu, L.A.; Faur, A.C.; Bolintineanu, S.L.; Salavat, M.C.; Maghiari, A.L. Advances in Diagnosis Approaches in Fungal Keratitis. Encyclopedia. Available online: https://encyclopedia.pub/entry/54873 (accessed on 17 May 2024).
Ghenciu LA, Faur AC, Bolintineanu SL, Salavat MC, Maghiari AL. Advances in Diagnosis Approaches in Fungal Keratitis. Encyclopedia. Available at: https://encyclopedia.pub/entry/54873. Accessed May 17, 2024.
Ghenciu, Laura Andreea, Alexandra Corina Faur, Sorin Lucian Bolintineanu, Madalina Casiana Salavat, Anca Laura Maghiari. "Advances in Diagnosis Approaches in Fungal Keratitis" Encyclopedia, https://encyclopedia.pub/entry/54873 (accessed May 17, 2024).
Ghenciu, L.A., Faur, A.C., Bolintineanu, S.L., Salavat, M.C., & Maghiari, A.L. (2024, February 07). Advances in Diagnosis Approaches in Fungal Keratitis. In Encyclopedia. https://encyclopedia.pub/entry/54873
Ghenciu, Laura Andreea, et al. "Advances in Diagnosis Approaches in Fungal Keratitis." Encyclopedia. Web. 07 February, 2024.
Advances in Diagnosis Approaches in Fungal Keratitis
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This entry is adapted from the peer-reviewed paper 10.3390/microorganisms12010161

Fungal keratitis represents a potentially sight-threatening infection associated with poor prognosis, as well as financial burden. Novel diagnostic methods include polymerase-chain-reaction (PCR)-based approaches, metagenomic deep sequences, in vivo confocal microscopy, and antifungal susceptibility testing. The ideal therapeutic approaches and outcomes have been widely discussed, with early therapy being of the utmost importance for the preservation of visual acuity, minimizing corneal damage and reducing the scar size. However, combination therapy can be more efficacious compared to monotherapy. Understanding the pathogenesis, early diagnosis, and prevention strategies can be of great importance. 

fungal keratitis mycotic keratitis antifungal therapy

1. Introduction

Fungal keratitis is a severe corneal infection characterized by the invasion by fungal organisms of the corneal tissue. The condition primarily affects individuals with compromised corneal integrity, often due to trauma, corneal abrasions, or the use of contact lenses. Among 105 known pathogenic mycotic species of keratitis, Aspergillus, Fusarium, and Candida are the most common and are accountable for 70% of the keratitis-causing fungal species [1].
Mycotic keratitis stands as a leading cause of ocular morbidity worldwide, with a higher incidence in tropical and subtropical regions [2][3]. A 2001 survey by the World Health Organization revealed that corneal blindness ranks as the second-leading cause of blindness, following cataracts [1]. Particularly in developing countries, ocular trauma and corneal ulceration are known as critical factors leading to corneal blindness.
Clinical manifestations of fungal keratitis include intense ocular pain, conjunctival hyperemia, photophobia, blurred vision, and epiphora. The infection may progress to the formation of corneal ulcers, leading to necrosis and potential scarring. Timely and accurate diagnosis is essential for appropriate management, typically involving a comprehensive eye examination, corneal scrapings for microbiological analysis, and the identification of the specific fungal pathogen [4].
The treatment of fungal keratitis involves a multifaceted approach aimed at eradicating the fungal infection, minimizing corneal damage, and preserving visual function. The choice of treatment depends on factors such as the severity of the infection, the specific fungal pathogen involved, and the response to initial therapeutic measures. Topical antifungal medications such as natamycin and voriconazole are frequently used. Voriconazole, in particular, has shown efficacy against a broad spectrum of fungi and is often considered a first-line treatment [5]. Amphotericin B is another potent antifungal agent which may be used topically. However, its use is sometimes limited by concerns about corneal toxicity. In severe cases, or when the infection is not adequately controlled with topical medications alone, systemic antifungal therapy may be considered. Oral voriconazole or itraconazole is commonly prescribed, especially when there is a risk of systemic dissemination. In cases of advanced or refractory infections, surgical interventions such as corneal debridement or, in extreme cases, therapeutic penetrating keratoplasty (PK) may be necessary to control the spread of the infection and salvage visual function [4][6].
Fungal keratitis often requires a collaborative effort between ophthalmologists, infectious disease specialists, and microbiologists. Regular follow-up visits are essential to assess the effectiveness of treatment and address any complications promptly. Early diagnosis, aggressive treatment, and close monitoring are critical components in achieving optimal therapeutic outcomes and preventing potential complications such as corneal scarring and visual impairment [7].
Preventative measures focus on meticulous eye care, particularly for contact lens wearers. Adherence to proper hygiene practices, regular lens cleaning, and avoiding overnight wear can mitigate the risk of fungal keratitis. Additionally, prompt attention to corneal injuries and the avoidance of environmental factors that may predispose individuals to fungal infections contribute to preventive efforts. Despite advancements in diagnostic and therapeutic modalities, the management of fungal keratitis remains intricate, requiring a multidisciplinary approach for optimal outcomes [2].

2. Diagnosis of Fungal Keratitis

Filamentous fungal keratitis typically manifests in young men involved in agricultural or outdoor activities. The fungi responsible for these infections do not breach an intact epithelium spontaneously; rather, invasion commonly occurs as a secondary consequence of trauma. Trauma stands out as the primary predisposing factor, affecting 40–60% of patients [8][9]. Other identified risk factors are prior ocular surgery, ocular surface disease, previous use of corticosteroids (topical or systemic), and contact lens usage [10][11][12]. Notably, a study on mycotic keratitis demonstrated the following: antifungal therapy or surgical intervention led to no response in patients with previous ocular surgery, a partial response in those with ocular trauma, a notable response in individuals with ocular surface disease, a universal response in contact lens users, and varied responses in patients with a history of corticosteroid use [5].
Filamentous fungal keratitis is predominantly caused by species like Fusarium, Aspergillus, Curvularia, and other phaeohyphomycetes. Environmental factors such as humidity, rainfall, and wind seem to influence the occurrence of filamentous fungal keratitis, contributing to seasonal variations in fungal isolation frequency and the specific fungal species identified [12][13].
Keratitis resulting from infection with Candida albicans and other related fungi is often associated with one or more ocular conditions, such as inadequate tear secretion or impaired eyelid closure, as well as systemic factors like diabetes mellitus or immunosuppression, which can predispose individuals to such infections. Additionally, this type of mycotic keratitis may develop in the presence of a pre-existing epithelial defect, either due to herpes keratitis or caused by abrasions resulting from contaminated contact lenses. The interplay of these local and systemic factors contributes to the susceptibility and occurrence of Candida-related keratitis [8].
The laboratory diagnosis of fungal keratitis has an important significance in facilitating appropriate and effective treatment. It has a role in conducting antifungal susceptibility testing to determine the responsiveness of patients to both traditional and newer antifungal agents. Typically, specimens for microbiological evaluation are obtained through corneal scrapings, while cases with deeper infiltrates or those resistant to standard procedures may necessitate corneal biopsy or suture biopsy. Traditional diagnostic approaches for fungal keratitis involve staining of the smear and culturing of corneal scrapings. However, contemporary molecular diagnostic methods, such as polymerase chain reaction (PCR), are nowadays valued due to their precision and rapidity. Additionally, real-time in vivo confocal microscopy (IVCM) corneal imaging is emerging as a valuable tool for early detection by identifying fungal hyphae in cases of fungal keratitis [2][4].

2.1. Microscopic Examination

The conventional diagnostic approach for keratitis involves the microscopic examination of corneal scraping specimens to detect fungal elements. Various stains are used for this purpose, including Gram, 10% potassium hydroxide (KOH) wet mount, calcofluor white, lactophenol cotton blue, Giemsa, acridine orange, and Periodic Acid Schiff (PAS) stains [9]. The identification of fungal hyphae using KOH is widely utilized for provisional diagnoses in many regions due to its cost effectiveness, straightforward procedure, ready availability, and ability to yield rapid results, facilitating a rapid start to antifungal therapy. The sensitivity and specificity of preparations involving KOH have been reported in the specialized literature as between 60% and 99.3% [14][15], and between 70% and 99.1% [10][13].
The effectiveness of staining methods varies depending on factors such as the specific stain employed, the skill of the medical doctor, and the nature and amount of the sample. When conventional techniques like corneal smear staining and culture yield no identifiable organisms, when the disease continues to progress in spite of maximum treatment, or when corneal involvement is too profound for scraping, resorting to a corneal biopsy becomes imperative. The use of specialized stains can improve the visibility of fungal hyphae and yeast. Several studies suggest that corneal biopsy specimens may exhibit greater sensitivity compared to scraping samples, possibly attributed to factors like deep stromal engagement by certain fungi or the restricted amount of corneal material obtained through scraping [16].
The microscopic examination of corneal scrapings in fungal keratitis aids in rapid and cost-effective presumptive diagnosis and leads to the direct visualization of fungal structures. Therefore, this method has often been used for the prompt initiation of targeted antifungal therapy, which can be crucial in preventing progression. Moreover, in developing countries, microscopic examination can be the only available diagnostic tool.

2.2. Culture Growth

While time-consuming, this method is indispensable for species identification and effective treatment. Additionally, it enables antifungal susceptibility testing to determine sensitivity to both traditional and newer antifungal agents. Culturing is considered the gold standard in fungal keratitis diagnosis due to its high specificity. Commonly employed culture media include Sabouraud’s dextrose/potato dextrose/blood/chocolate/thioglycolate agar. Despite its reliability, culture results may take over a week to exhibit results, potentially delaying the diagnosis. The corneal material has to be spread out as thinly as possible on the slides in order to facilitate visualization of the fungal hyphae or yeast cells. Other limitations include low sensitivity rates, the necessity for an experienced microbiologist for result interpretation, and the challenge of distinguishing between species that exhibit morphologically similar growth. These considerations show the need for a comprehensive approach that incorporates various diagnostic methods to overcome the limitations associated with culture alone [14][17].
The failure of traditional methods like clinical evaluation, corneal scrapings, and initial culture can result in suboptimal management, leading to failure in healing and visual impairment. A novel approach involves the endorsement of repeat cultures as a diagnostic and prognostic tool after initiating the treatment. A secondary analysis of data from the mycotic ulcer treatment trial (MUTT)-1 (milder, smaller ulcers) [18] and MUTT-2 (severe ulcers) [19] demonstrated that positive repeat cultures performed six days after treatment initiation were linked to impairment of visual acuity at the three-month mark, larger scar dimensions, and an elevated incidence of perforation and/or the requirement for therapeutic PK. Consequently, a repeat culture at day six serves as a crucial prognostic indicator, signaling the need for close monitoring, potential adjustments to the treatment, and consideration of early surgical interventions like PK or lamellar procedures such as therapeutic deep anterior lamellar keratoplasty (DALK) in positive cases [6][20]. These repeat cultures play an important role in evaluating the effectiveness of both conventional and newer antifungal agents. Consequently, sixth-day cultures are now recommended as a crucial prognostic tool, and ongoing research in this direction is likely to further establish their significance [21].
While culture is considered the gold standard for the diagnosis of mycotic keratitis, its main disadvantage is that it may take several days to weeks to receive a result and, therefore, it can withhold prompt treatment, which is crucial in fungal keratitis.

2.3. In Vivo Confocal Microscopy

IVCM represents an innovative and noninvasive technique used for analyzing the cornea, using a series of pinhole apertures to create optical sections. This technology shows each corneal layer, similar to in vitro histochemical techniques. Fungal keratitis, characterized by nonspecific clinical features, poor yields on scraping specimens, variable sensitivity of culture results, and the extended time required for culture growth, often leads to delayed diagnoses and suboptimal treatment outcomes. IVCM addresses these challenges and offers the additional benefit of being noninvasive [22]. In addition to diagnosis, IVCM may also be used to monitor the response of fungal keratitis to treatment. After 1 month of antifungal therapy to a patient with infection with Alternaria alternata, IVCM demonstrated a significant reduction in inflammatory cells and showed the presence of hyper-reflective scar-like tissue and the absence of branching hyphal infiltrates in the affected cornea [2].
Studies on IVCM in infectious keratitis have demonstrated promising results. Kanavi used tandem scanning–IVCM and reported high sensitivity and specificity percentages for mycotic keratitis (94% and 78%, respectively) [23]. In a study by Chidambaram et al., a laser-scanning confocal microscope achieved a sensitivity of 85.7% and a specificity of 81.4% in detecting fungal filaments [24]. A few advantages include being a noninvasive technique and the early identification of fungi, as well as the monitoring and guidance of treatment. IVCM also has limitations, including being a contact procedure, requiring a cooperative patient in the symptomatic stage, higher expenses, and restricted availability, and the incapacity to identify organisms at the species level currently limits its application as a primary diagnostic approach.
IVCM is a noninvasive technology that leads to the direct observation of fungal elements, such as hyphae and spores, and aids in the diagnosis, management, and follow-up of cases with mycotic keratitis. Although very promising, it still has its disadvantages, such as the need for an expert operator and patient cooperation.

2.4. Antifungal Susceptibility Testing

As antifungal resistance increases and new antifungal agents are introduced, antifungal susceptibility testing (AFST) and minimum inhibitory concentration (MIC) determination play a crucial part in the effective treatment of mycotic keratitis. The primary objective of AFST is to provide important information for clinicians regarding the susceptibility before and during treatment, or a resistance phenotype related to a particular combination of organism and antifungal agent. While the treatment of choice for various types of fungi can be empirically assumed based on proper pathogen identification, susceptibility testing becomes particularly useful when invasive mycotic infections are present, when developed drug resistance is suspected, or in patients unresponsive to treatment [2].
Two globally acknowledged committees, the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (EUCAST), have established phenotypic assays for in vitro AFST based on the broth dilution method for Aspergillus and Candida species [25][26][27]. The MIC is the lowest concentration of an antimycotic agent that inhibits the visible growth of a microorganism after a defined period of incubation. It is a key parameter in AFST, providing information about the effectiveness of an agent against a specific fungi. CLSI has provided protocols on MIC values for yeasts, while EUCAST has set MIC values for various antifungal agents against specific Aspergillus and Candida species. However, comprehensive information regarding MIC breakpoints for other species is still needed.
AFST, performed in clinical microbiology laboratories to assist in selecting the appropriate treatment, has demonstrated a connection between susceptibility and the response to treatment [28][29]. In a recent study that determined the MICs of natamycin and voriconazole on isolates from mycotic keratitis, Lalitha et al. demonstrated that natamycin had greater breakpoint values against all specimens except for Fusarium spp., while voriconazole had the lowest breakpoint value targeting Aspergillus species. They also showed that the greater the MIC breakpoint value, the greater the odds of developing corneal perforation [30]. Saha et al. assessed AFST using the disk diffusion method. They observed that Aspergillus spp. and Fusarium sp. exhibited higher sensitivity to voriconazole than natamycin, while amphotericin B showed effectiveness against yeasts [30]. Patil showed variable MIC against Candida with a range from 1–2 μg/mL for C. albicans [31], while Salvosa reported that MIC can be as high as 150 μg/mL for C. parasilopsis [32].
AFST plays a pivotal role in guiding the effective management of fungal infections and is integral to optimizing patient outcomes. Utilizing AFST allows clinicians to identify the most appropriate antifungal therapy tailored to the specific susceptibility profile of the infecting strain.

2.5. Molecular Diagnostic Techniques

2.5.1. Molecular Diagnostic Techniques Applied to Isolates Derived from Cultures

Molecular diagnostic techniques have revolutionized the rapid diagnosis of fungal keratitis, using PCR-based approaches. They play an important role in enhancing the accuracy and efficiency of identifying cultured organisms in cases of fungal keratitis. PCR is a commonly employed molecular method that amplifies specific DNA sequences, allowing for the rapid and sensitive detection of fungal pathogens. PCR-based assays, such as species-specific PCR and multiplex PCR, enable the differentiation of various fungal species and strains directly from cultured samples. DNA sequencing is another powerful technique, providing detailed information about the genetic makeup of the isolated organisms. Sequencing methods, including Sanger sequencing and next-generation sequencing (NGS), facilitate the identification of fungi at the species level, even in cases of complex and mixed infections [33]. Additionally, real-time quantitative PCR (qPCR) allows for the quantification of fungal DNA, aiding in assessing the severity of the infection [34]. These molecular techniques not only streamline the identification process but also contribute to a deeper understanding of the genetic diversity and epidemiology of fungal keratitis, guiding clinicians in tailoring appropriate antifungal treatments.
Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a method used for identifying pathogens within minutes [35]. Initially intended for bacterial organisms, it is now thought to be a tool for identifying fungal isolates, particularly yeasts and some genera of filamentous fungi [36]. A study found that this technique, used to detect the etiological spectrum of infectious keratitis, accurately identified pathological microorganisms in 51%, including 100% of culture-positive cases, except for 2% with polymicrobial growth [37]. These innovative modalities aid in identifying the exact species involved in the infection and facilitating appropriate treatment.
The internal transcribed spacer (ITS) region is currently believed to be a sequence with great potential for identifying the widest possible range of fungal species, and is nowadays used as a universal DNA barcode for fungal groups [38].

2.5.2. Molecular Diagnostic Techniques Directly Applied to Clinical Samples

Metagenomic deep sequencing (MDS) is nowadays known as a promising approach for better diagnostic sensitivity and accuracy [39]. DNA-sequence-based methods are used for the more rapid species identification of an organism [40]. Lalitha et al. reported their experience with MDS in 46 corneal ulcer cases, evaluating the specificity and sensitivity of traditional methods and DNA and RNA sequencing using latent class analysis (LCA). The sensitivity of MDS was found to be 74%, outperforming KOH/Gram stains (70%) and cultures (52%). On LCA, RNA sequencing demonstrated 100% sensitivity and specificity for bacterial keratitis and 100% sensitivity and 97% specificity for fungal cases [41]. As it is not yet FDA approved, genotyping is performed only in selective cases, but it holds promise in distinguishing a causative pathogen from colonization or contamination [42].
Custom tear proteomic approaches might have an essential role in the future treatment of fungal corneal disease [43]. Genomic approaches, mainly built on distinguishing amplicons of ribosomal RNA genes, are nowadays adopted in clinical practices. The metagenomic approach utilizes 16S rRNA genes to track dynamic transformations in conjunctival flora in mycotic keratitis [44][45]. Diagnostics based on 18S rRNA target enrichment sequencing show potential for diagnosing fungal corneal infections [46].
The PCR technique has the highest positive detection rate overall in cases with culture- or smear-negative results. Molecular characterization can distinguish various species of fungi and can recognize rarer species of fungi, which may pose a problem during diagnosis using only traditional methods. Various molecular methods are used for diagnosing and identifying causative agents in fungal keratitis, including traditional, nested, real-time, multiplex, and conventional PCR followed by enzymatic digestion, sequencing, single-strand conformation polymorphism (SSCP), next-generation sequencing combined with computational analysis dot hybridization, and high-resolution melting analysis [47][48][49][50][51]. A study had shown an important association between culture-proven fungal keratitis and multiplex PCR, reporting 94.1% diagnosis for Fusarium, 63.6% for Aspergillus fumigatus, and lastly, 100% for Aspergillus flavus [47]. The significance of precise fungal detection using molecular diagnostic methods, such as PCR, for optimal management and an improved therapeutic effect has been emphasized [52]. PCR cannot be used to monitor the response of the patient with fungal keratitis to antimycotic therapy because it is cannot differentiate viable from nonviable fungi [39].
The rapidity and accuracy of PCR diagnostic methods advocate for their application in the diagnosis of mycotic keratitis. Although not affordable in many clinical centers in developing countries, they should become part of the diagnosis algorithm alongside microscopic evaluation and cultures. MALDI-TOF MS is a novel diagnostic method, which may be reliable and easy to use. It exhibits both high sensitivity and specificity, but has yet to identify and distinguish related fungal species. MDS is a new technique for the diagnosis of fungal keratitis that is able to identify any organism in a single assay.

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Subjects: Ophthalmology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Laura Andreea Ghenciu
,
Alexandra Corina Faur
,
Sorin Lucian Bolintineanu
,
Madalina Casiana Salavat
,
Anca Laura Maghiari
View Times: 69
Revisions: 2 times (View History)
Update Date: 18 Feb 2024
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