(a) Fundus photo of a patient with Candida albicans infection shows chorioretinal infiltration with mild vitritis. (b) OCT image scanned along the green line in (a) shows hyperreflective lesion over retina. (c) In fluorescein angiogram, hyperfluorescence at chorioretinal lesion and diffuse leakage from disc and retinal vessels are seen
Fundus photographs showing choroioretinal infiltrates at inferonasal periphery (a) or at macula with hemorrhage (b) in a patient with Candida tropicalis fungemia. (c, d) Ultrawide field retinal images taken 3 years later show multiple chorioretinal atrophic lesions
(a) Ultrawide field retinal image shows yellow-whitish chorioretinal lesion at temporal periphery with vitreous involvement. (b) A week later, the chorioretinal lesion at temporal periphery became a large fluff ball, and new chorioretinal lesion is seen superior to disc. Fundus is more obscured by severe vitritis. The patient was later diagnosed as Candida albicans infection based on the vitreous culture
Candida endophthalmitis. (a) Confluent multiple chorioretinitis lesions and retinal hemorrhage at macula. (b) Fluff ball appearance of vitreous exudate. (c) Flame-shaped retinal hemorrhage and Roth spots. (Courtesy of Prof. Joo Yong Lee)
Fundus photographs and spectral-domain optical coherence tomography (OCT) images in a patient with Candida albicans infection. (a, b) Fundus photographs show a creamy lesion extending to the vitreous as well as multiple yellow-whitish chorioretinal infiltrates. (c, d) OCT images scanned along the green lines show a well-circumscribed, dome-shaped hyperreflective lesion overlying the retina. In addition, (d) shows a subretinal lesion corresponding to yellow-whitish infiltration with hemorrhage in fundus photograph. (Courtesy of Prof. Joo Yong Lee)
Initial symptoms are usually scarce or very mild and include blurred vision with mild ocular discomfort, floater, photophobia, and injection (Donahue et al. 1994). As intraocular candidiasis may show indolent course, fundus examination is recommended in all patients with candidemia, especially in those with higher risk of ocular involvement. Other signs of intraocular candidiasis include lens abscess, vitreous abscess, intraretinal hemorrhage, and Roth spots (Fig. 21.4). In addition, Candida is also the most common etiology of fungal keratitis, taking up nearly half of all culture-proven fungal keratitis (Galarreta et al. 2007). Prior history of ocular trauma with vegetable material, ocular surface disease, and penetrating keratoplasty are known risk factors.
Diagnosis
Diagnosis of systemic candidiasis may be assisted by the identification of fungus on direct microscopic examination or its growth in biological samples. Yeast growth in respiratory sample or urine should be interpreted with caution considering the normal colonization, but growth of candida in blood sample strongly supports systemic infection by candida.
In the diagnosis of intraocular candidiasis, recognition of characteristic fundus findings and thorough review of clinical history and medical status of a patient are fundamentally important, and laboratory test supports the diagnosis. Some fungal antigens or metabolites have been investigated for their efficacy in the diagnosis of systemic candidiasis, but they are not commonly employed in real-world clinical practice.
In case with significant vitreous involvement, vitreous fluid collection by pars plana vitrectomy for both diagnostic and therapeutic purposes allows possible isolation of the fungus. Sensitivity of vitreous culture in the suspected cases of endogenous fungal endophthalmitis is about 50% (Martinez-Vazquez et al. 1998). Polymerase chain reaction (PCR) can be applied to vitreous sample for fungal infection, and recent studies suggested promising role of PCR in the diagnosis of candida endopthalmitis (Anand et al. 2001; Okhravi et al. 1998) because PCR is more sensitive and rapid compared to conventional methods. Recently, broad-range PCR techniques, which uses primers and probes for the conserved regions in the ribosomal DNA of fungi of many species (18S or 28S rDNA) can be performed with ocular fluids to diagnose intraocular fungal or bacterial infection (Sugita et al. 2013). They can provide evidence of the presence of fungal infection in the eye but are not able to identify the species or strains of fungi.
Aspergillus
Pathogenesis
Aspergillus is a filamentous fungus with saprophytic feature. It is usually found in soil, air, plant, and decaying organic material. Most of human infections are caused by Aspergillus fumigatus followed by A. niger, A. flavus, or A. clavatus, although more than 200 species have been identified. The most common route of transmission to the human host is via inhalation into the pulmonary alveoli and paranasal sinus (Bakri et al. 2010). Aspergillus is normally isolated from the skin and mucous membranes including the conjunctiva.
There are three main forms of Aspergillus infection: allergic bronchopulmonary aspergillosis, aspergilloma, and invasive aspergillosis. The first two forms are confined to bronchopulmonary or sinus lesions. However, mainly in immunocompromised individuals, invasive aspergillosis occurs showing further dissemination into various organs such as skin, brain, kidney, gastrointestinal tract, myocardium, liver, spleen, and eyes.
Clinical Features
Ultrawide field retinal image of a patient with disseminated aspergillosis. (a) Right eye shows multiple yellow-whitish chorioretinal lesions with mild vitritis. (b) Left eye shows superior large fluff ball with satellite vitreous opacities and more severe vitritis
There are some features of chorioretinitis in ocular aspergillosis compared with candidiasis. There are usually only one or two lesions in Aspergillus infection, whereas chorioretinitis by Candida species often presents with multiple lesions. Rao and Hidayat described histopathologic features of enucleated eyes with intraocular candida and Aspergillus infection (Rao and Hidayat 2001). Extensive outer retinal necrosis and choroiditis with subretinal/sub-RPE involvement was usually noted in aspergillosis cases, whereas vitreous was the main focus of inflammation in Candida. In addition, fungal invasion along the retinal vessel or choriocapillaris, which causes retinal or choroidal infarction, was usually noted in aspergillosis cases but not in candidiasis (Jampol et al. 1988). Patients’ history may also be helpful in differentiating etiological fungal agent. Intraocular fungal infections in patients with a history of gastrointestinal surgery, hyperalimentation, or diabetes are more likely to be caused by Candida species, while those with the history of organ transplantation or cardiac surgery are prone to Aspergillus (Rao and Hidayat 2001).
Diagnosis
As in candidiasis, clinical diagnosis of (disseminated) aspergillosis based only on clinical features or history is difficult, and high clinical index of suspicion is important. Direct examination and culture testing in biological material such as blood or bronchoalveolar lavage are helpful in reaching a correct diagnosis. Pulmonary computer tomography scan or detection of galactomannan antigen, which is a component of the Aspergillus cell wall, by ELISA can also be helpful.
Gold standard for the ocular aspergillosis diagnosis is the identification of fungus in ocular fluids through isolation and culture, but because of more frequent location of Aspergillus in outer retina or subretinal space, the result is often negative. As described earlier, PCR enabled increased sensitivity compared to conventional culture methods as well as shorter time for diagnosis of fungal endophthalmitis (Anand et al. 2001).
Cryptococcus
Ocular cryptococcal infection is usually caused by Cryptococcus neoformans. Most common source of infection is dropping from birds, especially pigeons, and the fungus is also isolated from soil, fruit, and plant. Inhalation of airborne spores of C. neoformans is the main route of infection in the human body, and they disseminate hematogenously most commonly to the brain, meninges, and spinal cord. Intraocular cryptococcosis usually occurs through direct extension from optic nerve sheath or hematogenously from the primary focus, but direct ocular involvement of cryptococcus is rare (Henderly et al. 1987). Normal host immune response is capable of managing C. neoformans infection, but immunosuppression, malignancy, AIDS, and systemic lupus erythromatosus are reported to be risk factors for systemic cryptococcocal infection.
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