Guest Editorial: Fungal Keratitis

Dr. Quresh B Maskati,
President SAO-POSA, President Cornea Society & ISMSICS, India
Past President AIOS, MOS, BOA , Consultant, Mombai, India

Introduction

In the South Asian region, public health planners usually concentrate on reducing the cataract backlog, which is undoubtedly huge. However, eye infections are a “silent epidemic”, recognised decades ago. By some reports, it is estimated that the number of corneal ulcers presenting to clinics in this region is 10-30 times compared to that in the Developed World. (1)(2)(3).

A vast majority of infective keratitis disables the younger population compared to senior citizens affected by cataract. It is therefore of paramount importance that the eye surgeons of the SAARC region must adopt a pro-active approach towards infective keratitis patients so as to prevent blindness due to the disease itself, or the sequelae and complications arising out of late / poor management of the disease. Several studies from our region have shown that we have an unusually high incidence of fungal keratitis compared to the West.

A landmark study from South India of almost 300 culture positive cases of corneal ulcers showed around 47% had bacterial, 47% had fungal and around 5% had mixed infections (4) These were the cases studied from 1991-1994. However, more recent studies, including studies amongst children with corneal ulcers have shown an increasing incidence of fungal keratitis compared to bacterial (4). Studies in Nepal showed a 17% incidence while Bangladesh showed a 36% incidence of fungal keratitis.

Clinical Significance

What does all this mean for an average ophthalmologist?

It means that each of us must have a high index of suspicion when treating infective keratitis with the possibility of fungal keratitis always at the back of the mind. We must try and scrape all corneal ulcers ideally, including those in children – if necessary under sedation or even general anaesthesia, so as to determine the exact etiology.

History and Examination

There are certain pointers in the history and examination findings that indicate the lesion more likely to be fungal:

1. History of trauma with vegetative matter. Farmers often suffer minor trauma due to the edge of leaves or husk of grains or any other vegetable matter falling into the eye. They brush it away or worse, they rub their eyes vigorously to reduce the itchiness, thus spreading the material even deeper into the abraded cornea.
2. The relative absence of symptoms compared to signs. The farmer carries on his work, in spite of redness, some watering and maybe some foreign body sensation as the symptoms are much less compared to an acute bacterial infection. Thus a typical bacterial corneal infection will report within hours or days to the nearest doctor, while a typical fungal infection patient may report a week or two weeks after the injury
3. If a patient has been treated for an infective keratitis with multiple antibiotics or even antibiotic steroid combination drops, which is not infrequent in our part of the world, chances are there is now an opportunistic infection with fungi.
4. On examination: fungal ulcers in the early stages have feathery margins with or without satellite lesions. Another clue is a dry, leathery surface of the lesion. Parts of the lesion may have raised edges or a raised surface. A hypopyon, if present, may be convex. Presence of pigment in the ulcer points to likelihood of dematiaceous fungi. It is also possible for a deep fungal abscess to exist with an intact epithelium (5).
5. Fungal keratitis however rarely presents with some or all the classical features enumerated above, making even experts go wrong at times. In fact, in the late stages, one may get a total corneal ulcer or abscess, with anterior chamber not visible. Such cases cannot be correctly diagnosed without laboratory tests

In the same landmark study alluded to in the introduction,(4) when a panel of corneal experts were asked to decide on clinical appearance alone whether an ulcer was bacterial or fungal, they were right only two thirds of the time!

Investigations

• Corneal scrape with direct microscopic examination: KOH mount. Use of 10% potassium hydroxide on a slide after scraping the ulcer is an easy, cheap and effective method of identifying a fungal corneal lesion with a specificity and sensitivity over 80% Other stains like Gram’s and Giemsa can also be used. There are several other staining methods like PAS, methenamine silver nitrate, calcofluor white etc. (5,6). Imunofluorescent staining is seldom required. However, many of these, besides the KOH and Gram’s stain are not very easy to perform for the average ophthalmologist.
• Corneal biopsy. Can be resorted to if a scrape is negative or there is a deep abscess with an intact epithelium. A burr can be used to remove the epithelium or a small diameter skin biopsy trephine can be used to access the material. The author prefers using a polybraided 6/0 or 7/0 suture on a needle which is passed through the abscess. The thread is then cut and the tiny pieces can be inoculated on culture media
• Culture of the scraping on various media. The commonest is Sabouraud’s dextrose agar. Others used are thioglycollate broth, sheep blood agar, chocolate agar, brain-heart infusion etc. (5)
• Confocal microscopy has been around for some time and is a non invasive tool for in vivo detection of fungi with a specificity and sensitivity of over 80% (4). However, it is expensive, not available outside some tertiary centres and requires some expertise of the person performing the investigation. Hence for all practical purposes it is beyond the scope of the average general ophthalmologist
• Other investigations: Polymerase chain reaction or PCR tests, electron microscopy. These are mentioned in passing being impractical for the average solo private practitioner in a rural area.

Types of Fungi found in ophthalmic infections

Broadly, they can be divided into the filamentous variety: the commonest being aspergillus and fusarium species and the dematiaceous fungi (causing pigmented fungal ulcers). The non-filamentous fungi include the Yeast species, which are commoner in the West (examples being Candida and Cryptococcus) are not as common in our region. (7)

Medical Treatment:

Unfortunately, fungal keratitis is more prevalent in developing countries rather than the West. The Multinational Pharma companies have not spent even a small fraction on research for newer and more effective anti-fungal treatment compared to that on antibacterial drugs.

The treatment has involved 2 classes of drugs since decades;

1. The Imidazoles such as ketaconazole, itraconazole (available for parenteral and oral use) and fluconazole (also available as eye drops). These are more effective against the yeast species and hence of little use in our region, though they are the most freely available. They can be given systemically in cases of scleritis, endophthalmitis and deep keratitis
2. The polyenes such as natamycin 5% which is available as eye drops in suspension form and injection amphotericin B which can be freshly made into eye drops (0.15%). Amphotericin B can be used as an anterior chamber wash and for intracameral injection in to the AC in cases of deep keratitis. Intravenous administration has poor ocular penetration and is associated with severe kidney toxicity. Topical drops have poor effect against fusarium and cannot penetrate an intact epithelium.

Natamycin 5% has the advantage that it is effective against aspergillus, fusarium and yeast. However, like amphotericin B, it penetrates poorly through an intact epithelium

Voricanozole:

This are commercially available as 1% eye drops in India and can be made from IV voricanozole in other countries. They belong to the azole group. The drops have a fairly good penetration and can be considered ‘broad spectrum’ as they are effective against Candida, Aspergillus and Fusarium.(7). However, results from the landmark MUTT trial from South India and from a similar study done at LVPEI Hyderabad showed that Natamycin was more effective compared to Voricanozole eye drops particularly against the fusarium species(4).

Studies from the RP centre in India have demonstrated efficacy of Voricanozole when given as an intrastromal injection (50 micrograms in 0.1ml of ringers lactate)in the clear cornea around the ulcer margin (8), at the level of the midstroma.

Povidone Iodine

This is an antiseptic agent, fairly cheap and freely available in our region. Many eye surgeons use this routinely either to paint the ulcer or prescribe it in the form of diluted drops made from the commercially available 5% or 10% solution. The concentration used ranges from 1% to 5%. It is a broad spectrum antiseptic effective against both bacteria and fungi and can be a useful tool in the initial treatment till a definitive diagnosis is made and specific therapy initiated.

Use of Collagen Cross Linkage

This fairly new treatment for microbial keratitis unfortunately does not work in fungal keratitis. A small trial conducted by the Aravind group in South India had to be abandoned due to the higher rate of corneal perforations in the fungal ulcers treated by this modality.

Surgical Treatment

• Keratoplasty, both deep lamellar and penetrating are the main surgical interventions for recalcitrant fungal keratitis or in those cases where there is actual or impending perforation. Penetrating keratoplasty is more commonly done. Though ideally it should be done early for better optical results, before the ulcer spreads to the periphery, in most cases, it is a treatment of last resort for total corneal abscess. This is because of several factors
• The patient has less symptoms than those with a bacterial ulcer, so often seek medical help lat
• Many are farm labourers and use herbal and tribal medicines in their eyes exacerbating the proble
• When finally brought to a tertiary centre and offered surgery, ignorance causes fear of surgery and results in refusal

1. Availability of corneal tissue is not uniform in our region with large areas and even countries with eye banking in infancy and imported corneas costing thousands of dollars – out of question for the poor patients who get these ulcers
2. Corneal glue. For ulcers with thinning or with small perforations, less than 2.5mm diameter, cyanoacrylate glue can be applied. In addition to helping reform the anterior chamber, the glue is fungistatic as well
3. Amniotic membrane transplant. For similar indications as above as well as for larger perforations, where corneal tissue is not available, amniotic membrane grafts can save the eye from possible phthisis

Conclusion

In our South Asia region, fungal ulcers form almost half of the infective keratitis seen in our population. Hence a high index of suspicion must be maintained when confronted with a corneal ulcer. We need to develop the good habit of doing a corneal scrape and studying the scraping under direct microscope with a KOH drop to rule out fungi or to do a corneal biopsy in cases where scraping is negative.

For medical treatment the drug of choice in our region is natamycin 5% suspension with some role for topical Voricanozole and amphotericin B in select cases. In cases where the ulcer is progressing in spite of therapy early resort to therapeutic keratoplasty may result in eradication of the infection and even restore vision if good quality tissue is used.

References:

1.Whitcher JP, Srinivasan. “Corneal ulceration —A Silent Epidemic”. British Journal of Ophthalmology 1997 : 81, 622-623

2.Gonzales et al, Incidence of Corneal Ulceration in Madurai District, South India, Ophthalmic Epidemiology. 1996, 3:159-166

3.Eric JC et al, Incidence of Ulcerative keratitis in a defined population from 1950 thorugh 1988. Archives of Ophthalmology 1993, 111: 1665-1671

4.Prajna VN, Prajna L, Muthiah S. Fungal keratitis: The Aravind experience. Indian J Ophthalmol 2017;65:912-9

5. Fungal Keratitis : Afonso and Rosa in “Cornea” Volume 2, page 1253-1263. Mosby, 1997
6. Sharma S, Silverberg M, Mehta P, Gopinathan U, Agrawal V, Naduvilath T J. Early diagnosis of mycotic keratitis : Predictive value of potassium hydroxide preparation. Indian J Ophthalmol 1998;46:31-5
7. Daoud Al-Badriyeh,Chin Fen Neoh,Kay Stewart, and David CM Kong Clinical utility of voriconazole eye drops in ophthalmic fungal keratitis Clin Ophthalmol. 2010; 4: 391–405
8. Namrata Sharma, Prakashchand Agarwal, Rajesh Sinha, Jeewan S Titiyal, Thirumurthy Velpandian, Rasik B Vajpayee Evaluation of intrastromal voriconazole injection in recalcitrant deep fungal keratitis: case series Br J Ophthalmol 2011;95:1735e1737.