Ocular candidiasis is an intraocular infection that occurs in association with candidemia. Most cases are endogenous infections resulting from hematogenous dissemination from systemic candidemia to the retinal and choroidal vessels. Exogenous infections due to trauma or surgery are rare in North America and Europe but more common in tropical regions.
The causative organism is most often Candida albicans. Non-albicans species such as C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei can also be responsible. Although non-albicans species account for 54.4% of candidemia cases, C. albicans infection carries the highest risk of developing ocular candidiasis.
In a review by Breazzano et al. of 38 studies involving 7,472 patients, ophthalmic screening after candidemia revealed chorioretinal lesions in 9.2% and endophthalmitis in 1.6%. Since the establishment of a classification system requiring vitreous involvement in 1994, the incidence of endophthalmitis has decreased to 0.9–1.2%. In Asian countries, the prevalence of Candida endophthalmitis is approximately 2.5 times higher than in Western countries (3.6% vs. 1.4%). Thirty percent of endogenous fungal endophthalmitis cases are bilateral.
The Infectious Diseases Society of America (IDSA) recommends routine ophthalmic screening for all patients with positive blood cultures for Candida. Ocular candidiasis may be asymptomatic and detected only by fundus examination1), and the detection rate of ocular lesions is higher when screening is performed 7 days or more after the first positive blood culture.
IDSA recommends ophthalmologic screening for all patients with positive blood cultures for Candida. Because ocular candidiasis can progress asymptomatically 1), it is important to undergo a dilated fundus examination even in the absence of subjective symptoms.
Since it develops following fungemia, systemic fever often precedes. The triad of floaters, history of IVH (central venous nutrition), and fever strongly suggests fungal endophthalmitis.
Unlike bacterial endophthalmitis, ocular candidiasis progresses relatively slowly over days to weeks. It is possible to observe the initial appearance and progression. Clinically, it is broadly classified into Candida chorioretinitis and Candida endophthalmitis.
Chorioretinitis
Focal white lesions: Single to multiple yellowish-white round lesions form in the chorioretina. They commonly occur in the posterior pole and may be accompanied by surrounding hemorrhage.
No vitreous involvement: Stage without extension into the vitreous. Often curable with systemic antifungal therapy alone.
OCT findings: In the retinal route, a hyperreflective mass confined to the inner layers; in the choroidal route, a subretinal lesion is observed2).
Endophthalmitis
Vitritis: Vitreous opacity progresses, forming a feathery fungus ball.
Fluff balls and string of pearls opacities: Characteristic vitreous findings described as “fluff balls” or “string of pearls” are observed 4).
Anterior chamber inflammation: May be accompanied by fibrin exudation or hypopyon. In advanced cases, mutton-fat keratic precipitates are seen.
When the lesion becomes chronic, exudative granulomas protrude into the vitreous, forming proliferative membranes that lead to tractional retinal detachment. Iris rubeosis and secondary glaucoma may also occur.
Systemic risk factors for candidemia and local factors promoting ocular metastasis are involved in a complex manner.
The main risk factors associated with candidemia and ocular candidiasis are listed below.
| Category | Main Risk Factors |
|---|---|
| Iatrogenic | IVH, central venous catheter, abdominal surgery, urinary catheter |
| Drug-induced | Immunosuppressants, broad-spectrum antibiotics, long-term steroid use |
| Underlying diseases | Diabetes, malignant tumors, AIDS, post-organ transplant |
Factors that increase the risk of developing ocular candidiasis include C. albicans infection, use of central parenteral nutrition, persistent candidemia, and neutropenia within 2 weeks before onset.
In recent years, an increase in ocular candidiasis has been reported in critically ill COVID-19 patients. Long-term steroid administration and immunosuppressive states trigger opportunistic infections3)4). In the ICU environment during the COVID-19 pandemic, the incidence of candidemia has been reported to increase approximately fivefold3).
In kidney transplantation, Candida contamination of organ preservation fluid can be a source of infection. Its incidence is reported to be 0.86–14.4% 1).
In severe COVID-19 patients receiving long-term high-dose steroids, central venous catheterization, or mechanical ventilation, the risk of candidemia increases, and cases complicated by ocular candidiasis have been reported3)4). If floaters or blurred vision appear after discharge, prompt ophthalmologic consultation is recommended.
The diagnosis of ocular candidiasis is made clinically, based on a comprehensive assessment of the patient’s history, risk factors, and fundus findings. The presence of risk factors that predispose to immunocompromised status is an important clue for diagnosis.
The diagnostic classification of ocular candidiasis is as follows2).
| Classification | Definition |
|---|---|
| Proven case | Fundus findings + positive vitreous culture |
| Probable case | Typical fundus findings + known systemic candidiasis |
Chorioretinitis is clinically diagnosed as deep localized white lesions, and endophthalmitis as cotton ball or string of pearls opacities with vitritis.
Differential diagnoses include bacterial endophthalmitis, ocular toxoplasmosis, sarcoidosis, and masquerade syndromes such as intraocular malignant lymphoma. Differentiation from diabetic retinopathy, hypertensive retinopathy, and Roth spots associated with hematologic malignancies is also necessary. When vitreous opacity becomes severe, these differentiations become difficult.
The principle of treatment is removal of the infection source and systemic administration of appropriate antifungal drugs. Local ocular therapy is added depending on the severity of ocular involvement.
If IVH is the source of infection, prompt removal of the catheter is necessary. Persistence of the infection source leads to prolonged ocular involvement 1).
In Japan, intravenous injection of fluconazole (Diflucan®), a triazole antifungal drug, is selected as the first-line treatment for Candida endophthalmitis. Fluconazole is water-soluble, has good penetration into the aqueous humor and vitreous cavity, and is effective against yeasts, especially C. albicans.
Antifungal therapy must be continued until retinal lesions become scarred, usually for 3 weeks to 3 months. Retinal infiltrates begin to gradually shrink within 1–2 weeks of starting systemic treatment, but therapy should be continued until the lesions are completely scarred even after switching to oral administration.
The IDSA guidelines recommend initial administration of echinocandins (e.g., micafungin) for patients with candidemia, but because echinocandins have poor intraocular penetration, a switch to fluconazole or voriconazole is necessary when ocular candidiasis is present2).
When the lesion extends to the macula, intravitreal injection of amphotericin B (Fungizone®) 5 μg/0.1 mL is considered effective (off-label use). Intravitreal injection of voriconazole 100 μg/0.1 mL is also an option 3).
Sakai et al. (2021) reported that intravitreal injection of liposomal amphotericin B (L-AMB) 5–10 μg/0.1 mL was performed a total of 9 times for C. glabrata endophthalmitis, resulting in improvement of vitritis and regression of chorioretinal lesions 2). L-AMB is considered less retinotoxic than conventional amphotericin B deoxycholate.
If systemic treatment is ineffective or intraocular proliferative changes have already progressed, vitrectomy is performed. The concentration of fluconazole in the irrigation fluid during vitrectomy is adjusted to 10–20 μg/mL (off-label use). In severe vitritis, early vitrectomy is desirable to reduce the infectious load and remove fungal abscesses.
In fungal endophthalmitis caused by Candida, visual prognosis is relatively good if appropriate treatment is given early. However, white lesions in the macula can cause vision loss. Advanced cases may lead to tractional retinal detachment or secondary glaucoma, and delay in starting treatment worsens the prognosis.
Most cases of ocular candidiasis are endogenous infections, i.e., hematogenous dissemination from infectious foci in other organs. With candidemia, fungi reach the eye via the choroid and iris-ciliary body, which are rich in blood flow.
Two routes have been proposed for intraocular dissemination of Candida2).
When fungi reach the choroid, they form exudative granulomatous lesions extending from the choroid toward the retina. Small round white lesions and small hemorrhages appear mainly in the posterior pole of the fundus, gradually becoming multiple and accompanied by vitreous opacities. Unlike rapidly progressing bacterial endophthalmitis, this condition forms distinct fundus lesions and progresses relatively slowly over days to weeks.
In the later stage, vitreous opacities progress, and feathery fungus balls appear. Furthermore, exudative granulomas protrude into the vitreous, forming proliferative membranes that lead to tractional retinal detachment. At the same time, inflammatory cells increase in the anterior chamber, with fibrin deposition and posterior synechiae, which may progress to rubeosis iridis and secondary glaucoma.
Conventional amphotericin B deoxycholate (AMB-D) raises concerns about retinal toxicity. Liposomal amphotericin B (L-AMB) is a formulation in which AMB is inserted into the liposomal bilayer, reducing toxicity to human cells while retaining antifungal activity.
Sakai et al. (2021) performed a total of 9 intravitreal injections of L-AMB 5–10 μg/0.1 mL for C. glabrata endophthalmitis, achieving regression of chorioretinal lesions while maintaining visual acuity of 20/162). In animal experiments using rabbits, histological retinal damage was observed in about one-third of cases with AMB-D, whereas no damage was reported with L-AMB.
With the COVID-19 pandemic, reports of Candida endophthalmitis have increased in the context of prolonged ICU stay, mechanical ventilation, and high-dose steroid administration.
Kaluarachchi et al. (2022) reported a case of Candida endophthalmitis complicated by cytomegalovirus infection after treatment for COVID-19 pneumonia 3). Diagnostic vitrectomy, intravitreal voriconazole, and intravenous liposomal amphotericin B improved visual acuity from hand motion to 6/18.
Fossataro et al. (2023) reported a case of bilateral Candida endophthalmitis after COVID-19 ARDS 4). Because vitrectomy was difficult to perform during the pandemic, treatment with intravenous liposomal amphotericin B was initiated based on clinical findings and multimodal imaging (SD-OCT, FA, ICGA), and scarring was achieved after 3 months.
The “rain-cloud sign” (full-thickness hyperreflective infiltrates) on SD-OCT is noted as a suggestive finding in Candida endophthalmitis 4). Even when culture or biopsy is difficult, multimodal imaging combining FA, ICGA, and OCT may aid diagnosis.
