Introduction

Infectious corneal ulcers, also known as microbial keratitis, are considered to be a significant cause of blindness, particularly in developing countries.¹ Microbial keratitis has several potential aetiologies that consist of bacteria, viruses, fungi, and protozoa.² With the exception of fungal keratitis, the rest are bacterial keratitis, herpes keratitis, and amoebic keratitis (inflammation of cornea), which is commonly seen in contact lens wearers.³ It may affect the superficial layers (superficial keratitis), which typically heal without scarring that affects vision, or deep layers (deep keratitis), which can result in scarring that can affect vision depending on its location.³ 

Fungi are typically opportunistic pathogens that rarely penetrate a healthy cornea, but they may cause infection if the patient is immunosuppressed, experienced physical trauma (especially vegetative material), or is undergoing topical steroid therapy or experiencing ocular surface disease.¹ 

Fungal keratitis is an infection which requires prompt and effective therapy and it is notoriously challenging to diagnose and treat.^2,4 It accounts for 40% to 50% of microbial keratitis overall worldwide, and the incidence of fungal keratitis has risen during the past 30 years.^2,5 Fungal keratitis is more common in tropical and subtropical countries, especially in developing countries, where the highest prevalence is found.^1,2,5-7 Without appropriate treatment, there is the risk of destruction of the cornea and endophthalmitis that leads to permanent vision loss.² 

Fungal keratitis, as compared to bacterial keratitis, has worse clinical outcomes.^5,6 The course of infection is typically chronic with high risk for complications and perforation. More than half of patients suffering from fungal keratitis end up losing their eyesight and live with monocular blindness.¹

This article tries to provide an overview of fungal keratitis with a focus on its aetiologic causes, diagnostic complexities, and therapeutic challenges. By increasing awareness and knowledge among healthcare professionals, it is hoped that early diagnosis, prompt intervention, and subsequent prevention of loss of vision from this disease can be encouraged.

Causes and risk factors

Fungal keratitis is a serious type of microbial keratitis that can lead to catastrophic vision loss.^1,2

Common fungal pathogens

Fungi are typically opportunistic pathogens that rarely infect an intact cornea but can infect when the cornea is breached.¹ Over 100 fungal species have been identified as the causal agent in a case of fungal keratitis, the most common perpetrators being Fusarium, Aspergillus, and Candida species, which are responsible for over 95% of infections globally.^2,3,5,6

Fungal keratitis aetiologic agents are divided into two broad groups: filamentous fungi (moulds) and yeast/yeast-like fungi.^1,7 

• Filamentous fungi are comprised of septate forms like Fusarium and Aspergillus (nonpigmented), and pigmented forms (phaeohyphomycetes) like Cladosporium, Curvilaria, Alternaria, and Lasiodiplodia^1,2,7 
• Filamentous non-septate fungi are Mucor and Rhizopus²
• Yeast and yeast-like fungi include Candida, Cryptococcus, and Geotrichum. Candida is the most common yeast causative of FK^1,2,7 

Less commonly reported pathogens, typically phytopathogens, can also cause ocular infections.⁵

Risk factors

Numerous elements can cause damage to the protective layer of the cornea, compromising the immune status of the host and making them more susceptible to developing fungal keratitis.² These include:

• Trauma: This is the most frequent risk factor, especially for tropical and subtropical climates.^6,7 Vegetative, soil, or dust trauma is of special significance.^2,6 Trauma to the vegetative tissue can inoculate fungal conidia directly into the stroma or damage the epithelium, allowing invasion. Field or agricultural work imposes a high risk due to potential exposure to vegetative material and soil^2,4,6
• Uses of contact lens: It is one of the biggest risk factors in developed countries and has accounted for an increase in FK cases.^2,4,7 Poor hygiene with contact lenses, including not cleaning them adequately, poor hand hygiene, overnight wear, and use with water significantly raises the risk.^2,4,6 Contact lenses potentially elevate risk by promoting microbial attachment and altering the corneal microenvironment. An epidemic of Fusarium keratitis in the United States and globally during 2005-2006 has been linked to a specific brand of multipurpose contact lens disinfecting solution²
• Ocular surface disease: Diseases on the surface of the eye, such as dry eyes, insufficient secretion of tears, and abnormal eyelid closure, are significant risk factors^1,2,6
• Age and gender: FK can occur at any age but is more frequent in middle-aged patients (20-50 years) and is more frequent in males, particularly those engaged in agriculture or outdoor exposures, as they are at a higher risk due to a higher incidence of trauma^2,5,6 
• Immunocompromised state: Immunocompromised state or severe systemic illness are frequent aetiologic factors.^1,2,6 These include infections such as HIV disease, hepatitis, and diabetes mellitus and systemic immunosuppressive therapy^2,6 

Clinical presentation

Fungal Keratitis (FK) typically presents in a subacute manner.^2,6 Both the clinical presentation and history of fungal keratitis may differ based on the infecting agent, be it a filamentous fungus or yeast.^{2 5} While clinical characteristics are helpful to establish a diagnosis, microbiological laboratory tests are required for confirmation and identification of the infecting agent.^1,5 

Symptoms

• Decreased vision or vision blurring^1,3
• Eye pain, typically sudden but milder than from bacterial or Acanthamoeba keratitis and not preceded by clinical signs^1,3,6 
• Redness or hyperemia in the circumcorneal ciliary flush pattern^1,2.6
• Hyperesthesia to light (photophobia)^1,2,6
• Profuse tearing or tearing from the eye^2,3,6 
• Grittiness²
• Blepharospasm²

The symptoms can progress to ulceration, opacification of the cornea, and, less frequently, endophthalmitis.

Diagnostic approaches

Accurate diagnosis of fungal keratitis (FK) is challenging but important to facilitate early management, which will prevent irreversible corneal damage and improve the prospect of recovery.^1,2,5 

Clinical examination

Diagnosis of suspected fungal keratitis starts with good history taking, including risk factors, antecedent events, and symptoms.

• Slit-lamp biomicroscopy findings: A wide range of common clinical appearances may be encountered while examining the anterior and posterior segments of the eye under high magnification and an intense beam of light. These may be:
  • Lid oedema, matted lashes, and blepharitis
  • Mucopurulent or purulent discharge
  • Conjunctival congestion
  • Epithelial defects
  • Corneal infiltration, noting its site, size, depth, and extent

It is not always simple to distinguish between bacterial and fungal aetiology based on clinical presentation alone.² This may postpone confirmation of the diagnosis, especially since the clinical appearance may mimic that of other conditions like bacterial keratitis, Pythium keratitis, or viral keratitis.^1,2,6

Laboratory diagnosis

Laboratory work is valuable in the diagnosis, confirmation and identification of the causative agents.^1,6 

Corneal scraping and microscopy: Scraping the cornea is better than swabbing because fungi penetrate deeper into the cornea, as well as bulk up fungi and debride the surface to allow better penetration of the drug. Microscopy of corneal smears or scrapings is an important initial diagnostic measure. They use varying staining methods to see yeast cells and fungal hyphae, which allows for early detection before culture results.² These methods include:

• KOH mount
• Gram stain and Giemsa stain

Culture techniques: Fungal culture is the most sensitive diagnostic technique for FK and is needed for confirmation of the diagnosis.^1,6 It identifies the causative organism, identifies mixed infections, and allows testing of in vitro antifungal susceptibilities.¹ Isolation on Sabouraud dextrose agar (SDA) and on blood agar is the reference standard in these techniques.⁵ 

Molecular diagnostics: These are essential diagnostic procedures that include PCR and in vivo confocal microscopy(IVCM).

• Polymerase Chain Reaction (PCR): PCR is a quick and accurate test for FK diagnosis that has several benefits, such as producing accurate results in 4-8 hours^1,2 
• Confocal microscopy: A noninvasive imaging method called in vivo confocal microscopy (IVCM) produces high-resolution, real-time images of the cornea at the microscopic level.⁶ It is able to identify filamentary fungal and yeast hyphae in situ in ocular tissue.^1,2 Even in the earliest stages of diagnosis, IVCM can be useful in detecting hyphal density.¹ However, it is not very reproducible when imaging the same place, is unable to distinguish between distinct filamentous fungal species, and may not have enough resolution when imaging smaller organisms with intricate infestations¹

Treatment strategies

Fungal keratitis must be treated with a multi-faceted approach that includes antifungal therapy, along with potential surgery in severe cases. 

Antifungal therapy

The primary treatment for fungal keratitis is antifungal therapy.¹ The duration of treatment is generally prolonged, typically lasting for at least 12 weeks, or ranging from 4 to 16 weeks, depending on clinical response.² 

Topical Agents:

• Natamycin (5%) – Drug of choice, most effective against filamentous fungi² 
• Voriconazole (1%) – Alternative with prolonged coverage, including yeasts as well as moulds² 
• Treatment is typically started with hourly instillations for the first 48 hours, and then gradually tapered in frequency based on clinical response² 

Systemic Antifungals:

• Systemic antifungals are reserved for some conditions, i.e., deep and progressive ulcers, limbal ulcers, scleritis, and endophthalmitis.² They are also used prophylactically in penetrating keratoplasty for fungal keratitis
• Intravenous or oral antifungals (e.g., amphotericin B, fluconazole) may be necessary for scleral or deeply penetrating infections² 

Targeted drug delivery: 

• Intracameral and intrastromal injections are examples that are designed to deliver sufficient levels of drug to the area of infection and are considered for deep fungal keratitis when maximum medical therapy is inadequate²

Since the majority of antifungal drugs are unable to penetrate the cornea, drug penetration and bioavailability limitations pose a serious challenge in the treatment of fungal keratitis. One of the main causes of subpar outcomes is inadequate penetration of the infection site.^{2 7} 

Surgical interventions

In situations where medical therapy is ineffective or complications develop, surgery may be required.

• Since antifungals have a restricted entrance point to the anterior chamber and cornea, one method for enhancing their penetration is to scrape the infiltrate and epithelium. Antifungal penetration is improved by regularly removing mucus and necrotic material with a spatula. Scraping the cornea reduces the fungal burden (debridement) and is used as a first step to obtain tissue for laboratory investigation
• The first surgical option for treating fungal keratitis is thought to be therapeutic penetrating keratoplasty. It is recommended when the ulcer is getting worse despite the best medical care or when the patient does not respond to treatment
• Corneal transplantation keratoplasty, becomes necessary in advanced cases when a corneal perforation is imminent or already occurring, or when a case is unresponsive to treatment. Even a biopsy can be performed using the removed corneal button from therapeutic keratoplasty
• Additional surgeries include: Incorporate anterior chamber washing for hypopyon cases that do not respond to conventional therapy, intravitreal antifungal injection or pars plana vitrectomy for endophthalmitis, and enucleation as a last choice for more severe cases

Challenges in management

Due to its nonspecific symptoms, lack of effective antifungal medications, resistance and poor therapeutic efficacy, high risk of recurrence, and consequences, fungal keratitis is a difficult illness that can delay diagnosis.^1,2,5 The symptoms, which can be more severe than those of bacterial keratitis, include blurred vision, discomfort, redness, and discharge. Inadequate diagnostic tools, staff, or insufficient experience can all lead to misdiagnosis.¹

Another factor contributing to treatment failure in some areas is the scarcity of effective antifungal medicines. A lack of concordance between in vitro and in vivo medication responses and challenges with sensitivity testing are two factors that contribute to therapeutic failure.¹ More than 30% of cases have been documented to fail basic treatment, and some first-line medications may not be effective against all fungal pathogens.^1,2,7 

Additionally, after the infection goes away, the disease frequently necessitates long-term monitoring and rehabilitation, which may include additional surgical operations like keratoplasty to improve eyesight. Patients must recognise potential problems and follow the recommended drug plan. All things considered, fungal keratitis is a dangerous and expensive illness that needs to be treated quickly and efficiently.

Summary

Fungal keratitis (FK) is a major cause of corneal blindness, particularly in tropical and subtropical regions. It is more common in young agricultural workers with low socioeconomic status and trauma from organic matter. Risk factors include contact lens wear, poor hygiene, recent ocular trauma, and a history of ocular surgery. Early diagnosis and treatment are crucial to prevent long-term complications. Diagnosis is challenging due to nonspecific symptoms and mild clinical signs. Laboratory tests like corneal scraping and culture can delay diagnosis. The lack of a simple, inexpensive point-of-care diagnostic test is a significant obstacle to improved health outcomes, especially in resource-poor settings. Treatment primarily involves antifungal medications, but these drugs have poor penetration and require prolonged treatment due to slow response. Severe cases often require surgical intervention, with risks of recurrence.