Elsevier

The Ocular Surface

Volume 28, April 2023, Pages 364-377
The Ocular Surface

Past, present, and prospects in microsporidial keratoconjunctivitis- A review

https://doi.org/10.1016/j.jtos.2021.08.008Get rights and content

Abstract

Ocular microsporidiosis comprises two entirely different spectra of disease as keratoconjunctivitis and stromal keratitis. Microsporidial keratoconjunctivitis (MKC) has been increasingly reported in the past two decades, probably due to raised awareness, simpler diagnostic procedures, and a better understanding of the clinical presentation. It is characterized by the presence of raised, coarse, punctate, multifocal, round to oval, greyish-white corneal epithelial lesions which usually evolve into nummular scars before resolution. Conjunctivitis seen is non-purulent and of mild-moderate intensity, with mixed papillary-follicular reaction. The mode of transmission and pathogenesis is poorly understood. Despite lack of inflammatory response, uncommon associations reported were- endotheliitis, corneal edema, limbitis, uveitis, and sub-epithelial infiltrates. There has been no consensus on the management of MKC. It varies from the use of multiple antimicrobial agents to simple lubricants. The majority of the disease goes underdiagnosed or misdiagnosed and treated as adenoviral keratoconjunctivitis, with topical steroids or anti-virals empirically. Changing trends have been noticed in the pattern of infection, possibly with increasing evidence of Vittaforma corneae as causative organisms, previously reported to cause stromal keratitis. An elaborate review of the past and present literature on MKC is provided in this review article, along with gaps in knowledge, and future directions of research.

Introduction

Microsporidia are eukaryotic unicellular, spore-forming organisms. They belong to the phylum Microspora and kingdom Protista [[1], [2], [3]]. Based on morphological and molecular studies, it has been reclassified as fungi recently [4]. It infects both vertebrates and invertebrates. Microsporidiosis occurs worldwide; the prevalence varies based on the geographical and demographical characteristics, and diagnostic methods used for diagnosis. In humans, it is primarily an opportunistic pathogen seen in people with acquired immunodeficiency syndrome (AIDS), organ transplant recipients, patients receiving immunosuppressive drugs, and also in immunocompetent patients. It can affect multiple organs; most common are the digestive tract followed by the eye, sinus and respiratory tract, muscles, kidney, and central nervous system [5].

The eye is the second preferred site of microsporidia infection, and the cornea is the preferred site irrespective of the immune status. The common manifestations are superficial epithelial keratoconjunctivitis and deep stromal keratitis [4]. In the 1990s, microsporidia keratoconjunctivitis (MKC) was mostly reported in individuals with AIDS; in the following decades, several reports were published in healthy individuals worldwide. This could be attributed to our better understanding of the clinical features, diagnosis, and disease course, distinguishing it from common differentials like adenovirus and Thygeson's superficial keratitis.

In this review, we summarize the existing literature on the risk factors, clinical features, diagnosis, and management of MKC and speculate the scope for further research.

Section snippets

Method of literature search

Primary literature search was conducted on PubMed and Google Scholar, and included search terms ‘microsporidia’, ‘microsporidia keratitis’ and ‘microsporidia keratoconjunctivitis.’ A secondary literature search was conducted by reviewing the references of the initially included articles. We included 224 articles published in the past five decades, between July 1970 and August 2020. Detailed analysis of only 6 clinical studies with more than 20 patients, particularly 2 randomized clinical trials

Epidemiology

Microsporidia is a parasite of mammals, arthropods, birds, and fishes; in the late 19th century, it gained popularity as a European silkworm disease, caused by Nosema bombycis [6]. In humans, the prevalence varies widely from 0 to 50% [7]. Using various staining techniques and molecular methods (Polymerase Chain Reaction), it has been increasingly diagnosed from the South-East and South Asian countries.

Ocular microsporidiosis was initially referred to as corneal nosematosis, with 2 cases of

The organism

Microsporidia have a wide range of hosts with the zoonotic or interspecies transmission, but it remains enigmatic due to the difficulties in culturing them in the laboratory. The prokaryotic features found in them include a lack of typical mitochondria, peroxisomes, and centrioles. The presence of primitive70S ribosomes, tiny genomes, and a fused 5.8S and 28S rRNA placed them under the bottom of the eukaryotic tree. Later, homologues for alpha and beta-tubulin phylogenies, mitochondrial hsp70,

Pathogenesis

Germination is a crucial step for infection and varies widely among species. It depends on the organism's adaptation to their host and external environment. Conditions that promote spore discharge are extremes of pH or change in pH, dehydration followed by rehydration, various cations and anions, mucin or polyanions, hydrogen peroxide, low dose ultraviolet radiation, and the calcium ionophore A 23 187. The germination inhibitors are magnesium chloride, ammonium chloride, low salt

Transmission and risk factors

The exact mode of transmission in ocular microsporidiosis is not known. Faeco-oral transmission, including sexual and waterborne routes, have been reported in intestinal microsporidiosis [33]. Microsporidial spores remain viable against desiccation in variable temperatures; several pathogenic microsporidia (E. bieneunsi, E. intestinalis, V. cornea) have been isolated from the surface and groundwater [34]. Thus, contaminated water, in addition to inadequate sanitary facilities, is a potential

Clinical features

MKC is often misdiagnosed and treated as an atypical or unusual case of adenoviral conjunctivitis. It is bilateral in immunocompromised patients. Bilateral involvement in healthy individuals is reported in 8–32% of instances [24,41]. Although simultaneous involvement is more common, a sequential involvement of the contralateral eye can be seen after an interval of 1 week–3 months [20,21,24,42]. Similar to any other case of keratoconjunctivitis, symptoms include redness, watering, irritation,

Differential diagnosis

Microsporidial keratoconjunctivitis is mostly mistaken for adenoviral keratoconjunctivitis and Thygeson SPK. The chief differentiating features are the laterality, corneal lesion type, and anterior chamber reaction (Table 2). Other uncommon differentials are dry eyes, HSV epithelial keratitis in the vesicular stage, acanthamoeba, and atypical mycobacterial keratitis.

Microbiology-direct smear examination

In patients with microsporidial keratoconjunctivitis, the corneal lesions are superficial and raised, which can be scraped easily using surgical blade #15 under topical anesthesia. Routine staining techniques in the ocular microbiology laboratory are adequate to detect microsporidial spores in corneal scrapings. (Fig. 7) [44]. The smear used for Gram stain can be decolorized and re-stained with modified Ziehl-Neelsen stain, thus obviating the need for another scraping. Many authors have used

Antibiotics

Fluoroquinolones (FQs) are structurally related to the antimalarial quinolone drugs, targeting topoisomerases lV and DNA gyrase enzymes. In vitro and in vivo studies have shown that 6 FQs are effective against Vittaforma corneae [73]. These are (ciprofloxacin 0.3%, moxifloxacin 0.5%, gatifloxacin 0.5%, levofloxacin 0.5%, ofloxacin 0.3% and norfloxacin 0.3%). These FQs have been successfully used initially in hourly or two hourly doses latter tapered according to clinical response, either as a

Microsporidial keratoconjunctivitis in immunocompromised individuals

MKC has been reported in immunocompromised patients with very low CD+4 counts and other AIDs- related comorbidities. Lowder et al. first reported MKC presenting as bilateral conjunctivitis, with diffuse punctate epithelial keratopathy persisting beyond 3 months [9]. Subsequently, Friedberg et al. reported 3 cases of AIDs with keratoconjunctivitis; these eyes had minimal conjunctival congestion despite severe corneal involvement and peculiar fusiform swelling and hyperemia in the inferior

Conclusion and future direction

Ocular microsporidiosis is not a new entity but is increasingly reported, possibly due to increased environmental pollution and awareness and improved diagnostic ability [85]. It affects immunocompetent individuals. Most of the published large series are from Asian countries. The lack of reports from other parts of the world raises the question of its global epidemiology. It is reported to be associated with exposure to soil and muddy water. There is a need for public health studies to confirm

FUNDING/SUPPORT

Hyderabad Eye Research Foundation, Hyderabad, India.

Financial disclosure

None.

Declaration of competing interest

None.

Acknowledgements

The authors would like to acknowledge Dr. Taraprasad Das, for evaluating the work critically for important intellectual content and assistance in language editing.

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