Year : 2020 | Volume
: 10 | Issue : 1 | Page : 12--17
Parasitic keratitis – An under-reported entity
Sumeeta Khurana, Megha Sharma
Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Department of Medical Parasitology, Postgraduate Institute of Medical Education and Research, SS Anand Block, Sector 12, Chandigarh - 160 012
Parasitic keratitis (PK) is unique entity among parasitic infections where corneal involvement could result from direct inoculation of the parasite via exogenous environment or spread via endogenous neighboring organs or as a result of immune-mediated damage secondary to a systemic parasitic infection. Most cases of PK are caused by Acanthamoeba spp. and Microsporidia spp. though few other parasitic agents can also lead to corneal involvement. Mimicking as other infectious and non-infectious causes of keratitis, PK often escapes detection. This review summarizes the predominant causes of PK along with the epidemiological, clinical and microbiological details of each. Though several gaps exist in our understanding of the prevalence of PK, the one thing for sure is that PK is on the rise. With advanced diagnostic modalities and enough literature on optimal management of cases of PK, it is now imperative that a strong clinical suspicion of PK is kept when examining a case of corneal pathology and adequate investigations are ordered.
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Khurana S, Sharma M. Parasitic keratitis – An under-reported entity.Trop Parasitol 2020;10:12-17
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Khurana S, Sharma M. Parasitic keratitis – An under-reported entity. Trop Parasitol [serial online] 2020 [cited 2020 Jun 5 ];10:12-17
Available from: http://www.tropicalparasitology.org/text.asp?2020/10/1/12/284619
Parasitic keratitis (PK) has been increasingly recognized globally as an important cause of ocular morbidity in the past two decades. The major contribution in the etiology of PK is made by Acanthamoeba and Microsporidia and few other parasitic pathogens such as Onchocerca and Leishmania have also been implicated in corneal pathologies. PK is characterized by a prolonged and intractable course because not only the clinical features are nonspecific but also the routine microbiological investigations are too insensitive to give a definite diagnosis. Masquerading as several other infectious and noninfectious cases of keratitis, PK per se, often evades clinical suspicion as it is thought of as a rare entity. Further, microbiological investigations to specifically look for PK are either not ordered or not optimal for clinching the diagnosis. Even the treatment of PK is problematical as the drugs are neither available commonly nor provide a quick relief. Prolonged duration of therapy, as both topical and oral agents, is usually toxic to the corneal epithelium and also faces the problem of poor compliance. Owing to these factors, PK has long been ignominiously labeled as difficult-to-diagnose and difficult-to-treat disease. However, diagnostic advances, especially those in molecular techniques and parasitic culture methodologies, have the potential to revolutionize the way PK is seen and dealt. The need of the hour is to generate awareness, among both the ophthalmologists and the microbiologists, about the extent of disease burden caused by PK and ways of identifying and managing it.
Acanthamoeba keratitis (AK) is the most common presentation of Acanthamoeba infection and is characterized by intensely painful corneal involvement with a sight-threatening potential. Being free-living ubiquitous protozoa, Acanthamoeba can survive in air, water, and soil easily owing to its resilient double-walled cyst form which remains dormant and withstand adverse environments for years. AK develops when sufficient inoculum of Acanthamoeba gains access to a disrupted corneal epithelium. This disruption of corneal epithelium may be caused by any source such as trauma or surgery, but abrasions caused by faulty contact lens usage have become the most important risk factor for AK in contemporary times. The faulty practices include suboptimal disinfection of contact lenses (CLs), washing lenses with tap water, and swimming with lenses on., Wearing of CL has been associated with 80%-93% cases of AK worldwide. This association is not surprising, as a steep increase in the incidence of AK was noticed in mid-1980s (a decade after the very first case of AK was reported in 1973), consequent to the growth of CL market in the Western world., Similarly, in developing Asian countries including India, though the major cause of AK remains ocular trauma by vegetative matter while working in the fields among the rural population, CL-AK is the major cause among urban population. The disease burden of AK is largely underestimated as the data on actual incidence are patchy and are limited to AK associated with CL use. The available estimated prevalence of AK among CL users is 0.2–0.3/10,000 CL wearers or 0.15–1.4/million population. Data from two large outbreaks of AK in the United States, reporting a ten-fold increase in the incidence (from 2/million CL wearers/year in 1988 to 20/million CL wearers/year in 2003) over 15 years, suggest that AK is rampant and increasing. Further, coinfection of Acanthamoeba spp. along with other bacterial, fungal, viral, and parasitic agents has been well-documented in polymicrobial keratitis and also in acting as an endosymbiont for them., Unfortunately, AK still remains an “orphan disease,” and prospective multicentric studies are urgently needed to give a better picture of its disease burden.
Severe excruciating pain is the hallmark of AK. The pain is too severe to be explained by keratitis alone and it is produced by radial neuritis, a feature that differentiates it from herpetic stromal keratitis. The pain is out of proportion to clinical signs of conjunctival hyperemia, lacrimation, and photophobia. Unlike most other causes of keratitis, symptoms of AK can last for weeks to months together. The corneal lesion typically consists of a unilateral, central hazy infiltrate surrounded by a ring-shaped periphery. Microerosions and microcystic edema with patchy anterior stromal opacities are seen in the early stages, while epithelial loss from the central cornea, stromal opacities, and perforation develop as the disease advances, leading to loss of vision if left uncontrolled.,
In vivo confocal microscopy can help to make a provisional diagnosis of AK, wherein cysts of Acanthamoeba can be visualized as well-defined, spherical, hyperreflective structures with double walls. The trophozoites are more difficult to identify as they appear similar to nuclei of keratinocyte and leukocyte., For microbiological investigations, corneal scraping serves the most commonly received sample; however, the yield is better with a more invasive sample like corneal melt button or biopsy. Samples such as lens, CL solution, and water used for CL wash can also be used to track the source of infection. Staining of smear has been one of the earliest investigational steps for AK diagnosis owing to characteristic morphology of Acanthamoeba. For fixed smears, modified trichrome (with cysts appearing bright pinkish red with ectocyst and endocyst against a blue background) was found to be the most discriminatory stain followed by Gimenez stain and Giemsa stain. For more rapid identification and to minimize artifacts from the background corneal tissue, fluorescent stains such as calcofluor white and acridine orange may be used. Culture, though difficult to obtain, remains the gold standard for AK diagnosis. Monoxenic culture consists of non-nutrient agar (NNA) with an overlay of log-phase Escherichia coli. For axenic culture, the amoebae are slowly adapted to grow in special media containing peptone, yeast extract, glucose (PYG medium) or other supplements. Although morphological examination of trophozoites and cysts formed the basis of conventional classification of Acanthamoeba, the current classification into 20 genotypes requires 18S rDNA sequencing., The specific region of 18S gene, named diagnostic fragment 3 (DF3), is the most commonly used target for identifying the genotype of Acanthamoeba.
Achieving medical cure is the first-line management. Various drugs have been used, often in various combinations, for the treatment of AK. A handful of studies, performing in vitro susceptibility testing on Acanthamoeba, reported chlorhexidine, biguanides, pentamidine isethionate, and phosphocholines to be most effective against AK., A combination of drugs, especially those with different mechanisms of action, has proved beneficial. The medical therapy consists of hourly instillation of eye drops for initial days followed by 3-hourly instillation. It takes more than 2 weeks for the initial response to occur and the treatment is continued for not <4–6 weeks and as long as 6–12 months. Therapeutic penetrating keratoplasty is considered if keratitis worsens (impending perforations, spread to the paracentral stroma) on drugs or if recurrence is noted despite aggressive medical therapy., The infected tissue is removed and replaced by donor tissue, bipedicle conjunctival flap, or cryopreserved amniotic membrane graft to restore the integrity of ocular surface., Intensive medical coverage of several months, both before and after the procedure, is needed to ensure full clearance of any residual Acanthamoeba cyst.
Microsporidia are a group of obligate, small, intracellular eukaryotes infecting both vertebrates and invertebrates. “Microsporidia” is a nontaxonomic term for organisms belonging to phylum Microspora under subkingdom Protista and are phylogenetically related to fungi.Microsporidia are ubiquitous and their spore-forming ability help in dissemination and surviving extreme environments. At least seven genera have been implicated in causing human microbial keratitis (MK) – Enterocytozoon, Encephalitozoon, Pleistophora, Trachipleistophora, Brachiola, Nosema, and Vittaforma. MK was first described in 1973 in a Sri Lankan boy who sustained ocular trauma by a goat; however, more cases were recognized in the 1990s when MK was seen in association with HIV/AIDS. MK was earlier thought to be primarily a disease of the immunocompromised individuals characterized by chronic epitheliitis that would cause a decrease in vision and would respond variably to fumagillin (topical) and albendazole (oral)., However, soon after the turn of the century, a large number of MK cases were reported in nonimmunocompromised individuals from India and Singapore. Contrast to classical cases of the 1990s, these newer forms of MK responded well to commonly used topical agents within few weeks. Interestingly, among 152 cases of MK reported from India, 40 (25.3%) had a history of ocular trauma, while among 124 cases of MK reported from Singapore, 25 (20.1%) had a history of CL. Microsporidia are generally transmitted by direct contact, and pets such as cats and birds, the natural hosts for Microsporidia, are source of infection. Cases increase during the monsoon season, thus mimicking adenoviral keratoconjunctivitis (KC), due to dissemination of spores through muddy water. Muddy-water exposure was identified as a risk factor in 50% of patients in the Singapore series of MK.
Superficial KC, seen both in immunocompromised and immunocompetent individuals, has features of photophobia, redness, pain, lacrimation, and decreased vision. On examination, coarse, raised, punctate, multifocal epithelial lesions are seen often masquerading as adenoviral KC. Central stromal edema with fine keratic precipitates may be present. Recurrent stromal infiltration with/without uveitis is seen mostly in immunocompetent patients. Rarely, MK can involve the posterior segment as well.
Microscopic examination can seal the diagnosis provided that specific stains are performed. Corneal scrapings and button and biopsy samples should be subjected to specific stains if clinical suspicion of MK exists. One of the most sensitive staining methods is calcofluor white along with 10% potassium hydroxide (seen under the fluorescent microscope) or the modified Ziehl–Neelsen stain. The characteristic nonbudding oval bodies appearing apple green in the former and pinkish red in the latter stain confirm the diagnosis. Other stains such as Weber's modified trichrome stain, Gram's stain, H and E, and Gomori methenamine silver may also be used. Culture is seldom performed as Microsporidia are fastidious organisms and require tissue culture facilities. Cell lines used for culturing Microsporidia include Madin–Darby canine kidney, E6, and rabbit kidney-13. An indirect-immunofluorescent assay was developed by Centers for Disease Control and Prevention, Atlanta, for detecting microsporidial spores in corneal scrapings. Species identification, earlier done by electron microscopic details, is now carried out by targeting 16S rRNA. Joseph et al. developed a pan-species 16S rRNA polymerase chain reaction (PCR) that has a sensitivity of 83% and specificity of 98%.
The presentations of MK range from self-limiting KC to aggressive stromal involvement not responding to antimicrobials. The efficacy of medical management depends on the immune status, degree of stromal involvement, and species of pathogen. While superficial KC responds favorably to topical fumagillin and oral albendazole, stromal keratitis is refractory to several drugs.In vitro susceptibility testing has shown good activity of fumagillin against Enterocytozoon bieneusi, Enterocytozoon cuniculi, Enterocytozoon hellem, Enterocytozoon intestinalis, and Vittaforma corneae and that of albendazole against Encephalitozoon spp. Fluoroquinolones have also shown promising activity in KC cases. Itraconazole, metronidazole, and propamidine isethionate have also been used with variable results. Surgical debridement is not needed in most cases of KC, and the use of steroids worsens the disease. For stromal keratitis, surgical debridement or keratoplasty may help in decreasing the organism load, while a combination of chlorhexidine (topical) and albendazole (oral) may prove beneficial.
Onchocerciasis or river blindness is endemic to Africa (stretching from Ethiopia to Senegal), six countries in Latin America, and Yemen in the Arabian peninsula., Unlike AK and MK, corneal involvement by Onchocerca volvulus is not via environmental seeding of the ocular surface but through the migration of the microfilariae to the cornea from neighboring structures of the eye through blood or nerves. As the microfilariae advances along the cornea, it may die, thus releasing its own antigens along with the release of bacteria Wolbachia that it harbors an endosymbiont. This leads to an intense immunological response characterized by punctate and sclerosing keratitis. Over years of exposure, such reactions accumulate to cause corneal opacity. This along with the involvement of optic nerve and autoimmune-mediated retinal degeneration often leads to irreversible loss of vision. Diagnosis depends on the visualization of microfilaria on histopathological examination of corneal tissue from a patient of endemic region. Medical management of onchocercal keratitis consists of simultaneous ivermectin (for microfilaria) and doxycycline (for Wolbachia). Ivermectin, however, is not effective against adult worms. Surgical correction is required for corneal opacity.
A handful of reports have documented keratitis associated with various forms of leishmaniasis. Three cases, documented before 1980, did not have any microbiological evidence of Leishmania from the ocular samples; however, keratitis was linked to systemic leishmaniasis.,, The first case in 1942 has interstitial and ulcerative keratitis in association with cutaneous and mucocutaneous leishmaniasis. The second case reported in 1968 presented with keratitis that resolved with steroid, atropine, and systemic treatment for cutaneous leishmaniasis. The third case in 1979 had bilateral keratitis that resolved after amphotericin B therapy for mucocutaneous leishmaniasis. In 2015, bilateral keratitis was reported from a patient of visceral leishmaniasis with HIV/AIDS; the aqueous fluid from this patient was positive for Leishmania PCR; however, the patient progressed to pan-ophthalmitis despite intrastromal amphotericin B injections. In 2017, Pradhan et al. also reported two Indian cases of keratitis in immunocompetent patients after post-kala azar dermal leishmaniasis.
Other Rare Causes of Parasitic Keratitis
Thelazia callipeda and Thelazia californiensis, the oriental eye worm, have been implicated in causing human keratitis. Although rare cases have been reported from the US and India, majority of cases (~500) have been reported from China alone. Mechanical removal of worm or its larvae from the corneal surface by thin forceps leads to clinical improvement. Precautionary measures such as control of fly vector and treatment of infected host animals in the endemic regions of China are advocated for the control of human thelaziosis. Similarly, Loa loa, the African eye worm, can invade cornea along its path of migration and cause keratitis.
Ocular demodicosis, infestation of the eyelids by mite Demodex, has been associated with immune-mediated keratitis and more than twenty cases have been reported from the world. The keratitis was mostly bilateral, stromal, recurrent, and refractory to antiviral agents though the slit-lamp picture was similar to herpetic keratitis. Interestingly, drastic response was seen within 1 week of cleaning the eyelids and killing the mites. Similarly, phthiriasis palpebrarum, the skin lice, can also rarely cause keratitis if it gains access to eyelids through contaminated towels or clothes.
Another free-living ameba, Balamuthia mandrillaris, has been isolated from the eye case of CLs of a patient suffering from keratitis of unknown etiology. However, a causation could not be established.
PK is unique entity among parasitic infections where corneal involvement could result from direct inoculation of the parasite through exogenous environment or spread through endogenous neighboring organs or as a result of immune-mediated damage secondary to a systemic parasitic infection. Although the true epidemiology is poorly understood for most agents of PK, the occurrence of PK reflects the habitats of the offending parasites and the habits and immune status of the human host. Knowledge of the geographical spread, especially those of endemic ocular diseases such as onchocerciasis and thelaziosis, may aid in making presumptive diagnosis, however, with the growing international travel to exotic places, military deployments, and human migrations, even the endemic diseases are being exported out to newer lands. All these components including immune status, habit of wearing CLs, exposure to muddy water, ocular trauma, and travel to endemic areas form an important part of history taking from a patient of PK.In vivo confocal microscopy can help in making a presumptive diagnosis of PK at the clinic provided that the ophthalmologist is well versed with the typical morphology of the offending parasites and the type of tissue damage caused by them. In diagnosing AK, sensitivity to the tune of 90.6% with a specificity of 100% has been reported by in vivo confocal microscopy which also contributed in reducing number of days to diagnose AK leading to favorable clinical outcome. Sophisticated equipment and expertise dependence are the drawbacks of the confocal microscopy and its use is limited when the dense infiltrates or scars come in the way of visualization. Microscopic examination of corneal scrapings stained with special stains provide an easy and rapid means of establishing diagnosis of most commonly encountered cases of PK owing to their typical morphology and staining properties. Culture not only is cumbersome but also does not provide a result in clinically relevant time frame. Molecular techniques such as PCR targeting specific genes have become the mainstay of confirming the presence of implicated parasite. Loop-mediated isothermal amplification also provides a simpler and quicker means of amplifying and detecting the parasitic DNA from corneal samples. A DNA dot hybridization assay was also developed by Huang et al. to simultaneous diagnose AK and MK directly from corneal samples. Another diagnostic development has been made using MALDI-TOF MS, wherein spectral profiles from Acanthamoeba isolates (including those obtained from AK cases) were used to create in-house database which were further validated for the reliable identification of Acanthamoeba spp. as well as its genotype. Management involves aggressive medical therapy as well as surgical debridement along with the treatment of the underlying systemic diseases whenever applicable. Being notorious for recurrence, the management of PK should be judiciously individualized and serially monitored.
Although several gaps exist in our understanding of the prevalence of PK, the one thing for sure is that PK is on the rise. With advanced diagnostic modalities and enough literature on optimal management of cases of PK, it is now imperative that a strong clinical suspicion of PK is kept when examining a case of corneal pathology and adequate investigations are ordered.
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