Fungal endophthalmitis is a disease in which various fungi migrate into the eye, causing intraocular inflammation and visual impairment. It is classified into endogenous (hematogenous endophthalmitis), which spreads hematogenously from an extraocular infection focus, and exogenous, which occurs after surgery or trauma. Most cases are endogenous; exogenous cases are rare. It accounts for a portion of infectious uveitis1).
The main causative organisms are Candida species (majority), Aspergillus species, and Fusarium species. Intraocular lesions are reported in patients with candidemia, but the frequency varies greatly depending on the definition and screening method. Unlike bacterial endophthalmitis, it progresses relatively slowly while forming distinct focal lesions in the fundus, making diagnosis often delayed. Endogenous fungal endophthalmitis can occur bilaterally6).
If prolonged, extensive retinal necrotic changes occur, and visual prognosis after treatment is poor. If tractional retinal detachment develops, surgery is required, but visual prognosis is often poor. Early detection and treatment are key to visual prognosis.
When the triad of “floaters + history of IVH (central venous nutrition) + fever” is present, strongly suspect fungal endophthalmitis. Floaters, blurred vision, and decreased visual acuity are common initial symptoms. Early ophthalmologic evaluation should be considered in febrile patients on IVH or those diagnosed with candidemia 2).
Since fungal endophthalmitis develops following fungemia, fever is always present. Early ocular symptoms include floaters, blurred vision, and mild visual loss, which objectively appear as fine dust-like vitreous opacities. As the disease progresses, photophobia, eye pain, and severe visual loss develop. About 30% of endogenous cases are bilateral, and the asymptomatic fellow eye may also harbor lesions.
Early stage: White lesions in the posterior pole
Small round white lesions: Single or multiple in the posterior pole. Borders are relatively distinct.
Small hemorrhagic spots: May be accompanied by punctate hemorrhages around the lesions.
OCT findings: Characteristic elevation penetrating the retinal pigment epithelium.
Symptoms: Mainly floaters, mild blurred vision, and mild visual loss. Progresses relatively slowly.
Intermediate stage: Vitreous opacities (fungus ball)
Multiple lesions: White lesions increase in size and number.
Feathery vitreous opacity (fungus ball): A characteristic finding where fungal masses form in the vitreous.
Progression: Worsening of visual acuity and blurred vision.
Anterior chamber inflammation: Accumulation of fibrin and inflammatory cells appears.
Late stage: Diffuse opacity and proliferation
Dense diffuse vitreous opacity: The fundus becomes difficult to visualize.
Exudative granuloma: Forms in the choroid and retina, protruding into the vitreous.
Proliferative membrane → tractional retinal detachment: Recovery of visual function becomes difficult.
Anterior segment complications: Anterior chamber fibrin, posterior synechiae, rubeosis iridis → secondary glaucoma.
Unlike rapidly progressing bacterial endophthalmitis (hours to days), fungal endophthalmitis progresses slowly over weeks to months while forming distinct focal lesions in the fundus. Systemic background such as history of IVH use, fever, and immunosuppression is also important for differentiation.
| Category | Risk Factor |
|---|---|
| Iatrogenic (most important) | IVH (central venous nutrition), major abdominal surgery, urinary catheter, immunosuppressants, antineoplastic drugs, long-term steroids, post-radiotherapy |
| Underlying diseases | Advanced malignancy, bone marrow/organ transplant, hematologic malignancies (leukemia, malignant lymphoma), AIDS, severe infections, diabetes, collagen diseases, heart disease |
| Others | Trauma, malnutrition, advanced age |
| Exogenous (rare) | After intraocular surgery, after ocular trauma |
IVH (central venous nutrition) is the most important risk factor. Skin commensal yeasts cause systemic infection via central venous catheters, leading to candidemia. Intraocular lesions have been reported in patients with candidemia, and the IDSA 2016 guidelines recommend early ophthalmologic evaluation2,3).
The IDSA 2016 guidelines recommend ophthalmologic evaluation early after initiation of treatment for candidemia2).
In patients with candidemia, intraocular lesions may be found even without symptoms, and the IDSA 2016 guidelines recommend early ophthalmologic evaluation after starting treatment2). However, there is debate regarding screening targets and the definition of endophthalmitis; decisions are made jointly by internal medicine and ophthalmology based on the patient’s general condition and ocular symptoms6).
In addition to the “triad (floaters + history of IVH + fever)”, confirmation of characteristic fundus findings (small round white lesions in the posterior pole, fungus ball, diffuse vitreous opacity) is important. Unlike bacterial endophthalmitis, it progresses relatively slowly, which aids in differentiation. It often develops some time after IVH is discontinued.
| Test method | Specimen | Characteristics |
|---|---|---|
| Fungal culture | Arterial blood, catheter tip, vitreous fluid | Essential for identification of causative organism and drug susceptibility testing. Provides definitive diagnosis but requires time for results. |
| β-D-glucan | Serum | Highly sensitive screening indicator for deep-seated mycosis. Can be detected even in culture-negative cases. |
| Candida antigen (CAND-TEC) | Serum | Candida-specific |
| Aspergillus antigen (GM test) | Serum, BAL | Aspergillus-specific. Useful in neutropenic patients. |
| PAS stain | Vitreous, aqueous humor, tissue | Stains fungal cell wall polysaccharides |
| Grocott stain | Vitreous, aqueous humor, tissue | Excellent for identifying fungal hyphae |
| Fungiflora Y® stain | Tissue | Fluorescent staining method |
| PCR (fungal) | Aqueous humor, vitreous fluid | High sensitivity and specificity; useful even with small samples. Attempted for identification of causative organisms. |
Bacterial endophthalmitis progresses rapidly over hours to days and presents with severe inflammation (hypopyon, intense eye pain). In contrast, fungal endophthalmitis progresses slowly over weeks to months and is characterized by relatively well-demarcated white lesions in the posterior pole or fungus balls. The presence of systemic risk factors such as IVH use, fever, and leukopenia is also an important differentiating point.
Especially when IVH is the source of infection, promptly remove the catheter. As long as the infection source remains, antifungal drugs may not be fully effective.
Start with medical treatment (systemic administration) and decide on the strategy while observing the treatment response. Retinal infiltrates begin to gradually shrink within 1–2 weeks after starting treatment, and continue until the lesions are completely scarred even after switching to oral medication. Usually, 3 weeks to 3 months of medication is required.
Candida endophthalmitis (first choice):
Aspergillus endophthalmitis:
| Class | Generic Name (Brand Name) | Dosage and Administration | Major Side Effects |
|---|---|---|---|
| Polyene | Amphotericin B (Fungizone®) | IV 0.75 mg/kg/day. Intravitreal 5 µg/0.1 mL (off-label) | Hepatorenal toxicity, anemia, bone marrow suppression |
| Triazole | Fluconazole (Diflucan®) | 200–400 mg/day IV or oral. Reduce dose in renal impairment | Liver dysfunction (elevated liver enzymes) |
| Triazoles | Itraconazole (Itrizole®) | 100–200 mg/day oral. Spectrum covers Candida spp. and Aspergillus. | Liver dysfunction |
| Triazoles | Voriconazole (Vfend®) | IV to oral switch. Effective against filamentous fungi (Fusarium, Aspergillus, etc.). | Liver dysfunction, visual disturbance (reversible, per package insert) |
| Echinocandins | Micafungin (Fungard®) | IV infusion 50–150 mg/day (once daily). Effective for aspergillosis. | Liver dysfunction, acute renal failure |
For cases that respond poorly to systemic treatment or when intraocular proliferative changes have already progressed, vitrectomy should be performed after consultation with other departments, if possible. When vitreous opacity progresses, early diagnosis and aggressive vitrectomy are desirable.
Although it varies depending on the severity of endophthalmitis, the type of causative organism, and treatment response, retinal infiltrates gradually begin to shrink within 1–2 weeks after starting systemic treatment. After switching to oral medication, treatment should continue until the lesion is completely scarred, usually requiring 3 weeks to 3 months of medication. In cases requiring vitrectomy, continued administration of antifungal drugs is necessary after surgery.
Candida species (especially Candida albicans), which are commensals on the skin and gastrointestinal tract, can breach the intestinal mucosal barrier or enter the bloodstream via central venous catheters due to IVH use, long-term antibiotic use, or immunosuppression. Once fungemia is established, the fungi reach the choroidal capillaries hematogenously and establish infection.
Sequence of lesion progression:
Fungal colonization of the choroid → invasion into the inner retina through the retinal pigment epithelium → formation of retinitis → spread into the vitreous cavity → fungus ball formation → formation of inflammatory proliferative membranes → tractional retinal detachment
In hosts with preserved immune function, fungal endophthalmitis progresses relatively slowly and forms well-defined focal lesions in the fundus. In contrast, in neutropenia, AIDS, or post-transplant immunosuppression, it progresses rapidly, and filamentous fungi such as Aspergillus and Fusarium are more likely to cause disease 6).
For fluconazole-resistant Candida glabrata and Candida krusei, selection of antifungal agents based on drug susceptibility testing (minimum inhibitory concentration: MIC measurement) is important 2,7).
Endogenous fungal endophthalmitis can occur in both eyes. If prolonged, it leads to extensive retinal necrotic changes, and the visual prognosis after treatment is poor. In patients with poor general condition, control of fungemia becomes difficult, and ocular symptoms may recur.
In endophthalmitis caused by filamentous fungi (Aspergillus, Fusarium), the use of intravitreal voriconazole (100 µg/0.1 mL) alone or in combination with systemic administration has been reported in case series 5). Accumulation of future dose optimization data is expected.
Regarding routine ophthalmologic screening for candidemia patients, systematic reviews have discussed its usefulness and the potential for overdiagnosis and intervention 8). Standardizing the target, timing, and definition of evaluation including asymptomatic cases remains a future challenge.
To address fluconazole-resistant Candida species, the importance of individualized treatment based on culture identification and MIC is increasing 2,7). When intraocular specimens are available, culture and molecular diagnostics should be combined with systemic testing to identify the causative organism.
