Review
The global incidence and diagnosis of fungal keratitis

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Summary

Fungal keratitis is a severe corneal infection that often results in blindness and eye loss. The disease is most prevalent in tropical and subtropical climates, and infected individuals are frequently young agricultural workers of low socioeconomic status. Early diagnosis and treatment can preserve vision. Here, we discuss the fungal keratitis diagnostic literature and estimate the global burden through a complete systematic literature review from January, 1946 to July, 2019. An adapted GRADE score was used to evaluate incidence papers—116 studies provided the incidence of fungal keratitis as a proportion of microbial keratitis and 18 provided the incidence in a defined population. We calculated a minimum annual incidence estimate of 1 051 787 cases (736 251–1 367 323), with the highest rates in Asia and Africa. If all culture-negative cases are assumed to be fungal, the annual incidence would be 1 480 916 cases (1 036 641–1 925 191). In three case series, 8–11% of patients had to have the eye removed, which represents an annual loss of 84 143–115 697 eyes. As fungal keratitis probably affects over a million people annually, an inexpensive, simple diagnostic method and affordable treatment are needed in every country.

Introduction

Fungal keratitis, also known as mycotic keratitis, keratomycosis, or oculomycosis, is a severe sight- threatening condition. This highly damaging corneal infection often leads to permanent blindness and eye loss.1, 2 The condition is most prevalent in tropical and subtropical locations and has been estimated to account for 20–60% of all culture-positive corneal infections in these climates.3 Fungal keratitis tends to be a poorly treated condition with very high morbidity.1, 2, 4 Corneal infections have been declared a silent epidemic,5 yet the size of this epidemic has never been carefully estimated.

Fungal keratitis occurs secondary to often minor ocular trauma in most cases. Infected individuals are frequently young, healthy agricultural or outdoor workers who experience an injury from organic matter such as during harvesting.2 Traumatising agents from a variety of plant and animal sources have been recorded, even dust particles.2, 4 As men make up a greater proportion of agricultural and outdoor workers, they are more prone to the disease than women.6 In one case series, nearly 4% of cases were found in children,6 although the vast majority of cases are seen in adults aged 20–50 years.7 Other reported predisposing factors for filamentous fungal keratitis include previous ocular surgery, ocular surface disease, contact lens use, previous use of corticosteroids (topical or systemic), and immunosuppressive conditions such as HIV/AIDS.2, 4, 8 Traditional eye remedies, which are often plant-based and non-sterile, can also introduce infection.9 Conversely, in temperate regions, ocular surface disease such as insufficient tear secretion and defective eyelid closure can predispose to candida and candida-like keratitis. Candida spp infections might superimpose on pre-existing Herpes simplex keratitis or corneal defects from contact lens wearing. Unsafe hygiene practices such as overnight wear and ineffective cleaning have been associated with fungal keratitis. Contact lens wearers of low socioeconomic status are at increased risk of developing the condition, attributed to a inadequate education about hygienic eye care and insufficient cleaning solution use.6

Fungal infections of the cornea are caused by more than 100 different species, although over 95% are caused by the filamentous fungi Fusarium spp and Aspergillus spp and the yeast Candida spp. Filamentous fungi are responsible for most fungal infections in tropical and subtropical climates, with yeast being more frequent in temperate climates. Corneal infections caused by filamentous fungi tend to have a worse prognosis than those caused by yeast species.2

Fungal keratitis typically presents subacutely with eye pain, followed by blurred vision, redness, excessive tearing or discharge, and photophobia. It progresses to ulceration, opacification of the cornea and, more rarely, endophthalmitis.10 Corneal perforations are common and five to six times more likely than in bacterial keratitis, and often result in the need for evisceration.1, 4 For the patient, the consequences range from visual impairment and blindness, to loss of the globe and disfiguration.1

The differential diagnosis includes fungal, bacterial, viral, amoebic, oomycete, or parasitic causes. Certain clinical features are suggestive of a filamentous fungal infection: firm or dry elevated slough, an irregular or feathery stromal infiltrate edge, satellite infiltrates, an immune ring, and endothelial plaques.2 A hypopyon (pus in the anterior chamber) might also be present. Because of the overlap in the clinical signs at presentation, it is often not possible to clinically distinguish fungal keratitis from other types of corneal infection.6, 11

Key messages

  • Microbial keratitis is an avoidable cause of usually unilateral blindness and sometimes eye loss; fungal (mycotic) keratitis is generally more difficult to diagnose and has a worse outcome than other types of microbial keratitis

  • Despite publication of more than 3600 papers about microbial keratitis, the annual incidence of fungal keratitis has never been ascertained; a minimum of 1 million cases of fungal keratitis occur annually—this number rises to over 1·4 million if culture-negative cases are assumed to be fungal

  • The highest annual incidence of fungal keratitis and the highest ratio of fungi versus bacteria as a cause of microbial keratitis occur in subtropical and tropical countries, predominantly in male agricultural workers

  • Calcofluor-white with florescence microscopy is superior in sensitivity to potassium hydroxide, Giemsa, lactophenol cotton blue, and Gram stain in the diagnosis of fungal keratitis

  • Fungal culture is essential for diagnosis, and more than 100 different fungal species are known to have caused fungal keratitis

  • Probably about 100 000 eyes are removed annually because of late diagnosis and poor therapeutic outcome

Corneal scrapings for direct microscopy and culture are required for definitive diagnosis, although other modalities might be helpful, including molecular methods and in-vivo confocal microscopy.2, 7 Sometimes a corneal biopsy is required. There is currently no point-of-care diagnostic test for fungal keratitis, which is major obstacle in improving health outcomes for the condition.

General trends and risk factors are widely reported, but there has been very little epidemiological research conducted in Africa, Asia, and central and South America to calculate its global incidence. The aim of this Review was to appraise the existing literature concerning the incidence of fungal keratitis, the optimal means of making the diagnosis, and to use the most reliable data to estimate the global burden of this condition.

Section snippets

Search strategies

We did a systematic literature review on the epidemiology of fungal keratitis from Jan 1, 1946, to July 26, 2019, using Embase, MEDLINE, PubMed, CINAHL, and Cochrane (search terms given in the appendix, p 1). Papers presenting incidence of fungal keratitis within a defined population were evaluated using an adapted GRADE score12 on the basis of the following features: diagnostic accuracy, study size (using a cutoff of >30 cases), decade of study, with more recent studies scoring higher, and

Epidemiology

Our epidemiology searches identified 3668 records, of which 397 were selected for full-text assessment after title and abstract screening. Duplicates were then removed, leaving 241 unique full manuscripts to be assessed for eligibility. We excluded 59 full-text articles for the following reasons: 33 were not related to the epidemiology of fungal keratitis, 16 did not present their original data, and seven presented data on bacterial keratitis only. This selection left a total of 187 studies

Diagnosis

Timely diagnosis of fungal keratitis can prevent irreversible corneal destruction and drastically improve the chances of complete recovery.26 Diagnosis of this disorder starts with a strong clinical suspicion.10 On presentation of a patient with suspected mycotic keratitis, a thorough history must be obtained, with a particular focus on symptoms, preceding events, and risk factors. A meticulous search for local ocular or systemic defects should follow and these should be managed to prevent

Conclusions

The annual global incidence of fungal keratitis has never been estimated. There are few epidemiological data from Africa, Asia, and Latin America on which to base country incidence. Variations within countries are also likely, partly because of climate, but also occupational risk factors, as seen in bacterial keratitis.55 Fungal microscopy and culture both have low sensitivity for fungal keratitis, and so estimates based on these diagnostic modalities underestimate incidence. Despite these

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