Continuing Education Activity

Fungal endophthalmitis is a rare disease of ocular inflammation caused by fungal infections from either endogenous or exogenous sources. Because the clinical symptoms vary greatly and overlap with other ocular pathologies, fungal endophthalmitis presents as a diagnostic challenge. This activity reviews the evaluation and management of fungal endophthalmitis and reviews the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Identify the etiologies for fungal endophthalmitis.
• Describe the common physical exam findings associated with fungal endophthalmitis.
• Review the appropriate diagnostic testing for fungal endophthalmitis.
• Summarize the importance of collaboration and communication among the interprofessional team to enhance care coordination for patients affected by fungal endophthalmitis.

Introduction

Endophthalmitis is a rare but severe disease of ocular inflammation involving vitreous or aqueous fluids and other intraocular tissues that can result in blindness. Fungal endophthalmitis is caused by intraocular fungal infections originating either exogenously from penetrating trauma and surgeries or endogenously from hematogenous spread. The highly variable clinical picture of fungal endophthalmitis presents as a diagnostic challenge as the features of the disease overlap with bacterial, non-infectious, and neoplastic etiologies.

A lack of clinical suspicion and the empiric use of corticosteroids without proper antifungal coverage increases the risk of significant visual loss. Therefore, it is imperative for healthcare providers to recognize fungal endophthalmitis and diagnose it early for prompt initiation of effective antifungal therapy.[1]

Etiology

Exogenous Endophthalmitis

Exogenous endophthalmitis is due to infectious pathogens of the ocular surface or external environment complicating intraocular surgery or from penetrating ocular injury or the contiguous spread from adjacent tissues. The three forms of exogenous fungal endophthalmitis are postoperative, posttraumatic, and fungal keratitis-derived.

In general, postoperative endophthalmitis is the most common type of endophthalmitis, accounting for 40%-80% of cases of endophthalmitis. It is rarely fungal, but Aspergillus and Candida species are the most commonly reported fungal organisms implicated in postoperative endophthalmitis.[2][3][4][5] Posttraumatic endophthalmitis is the second most common type, accounting for 25% of cases of endophthalmitis.[6] Bacteria are responsible for most cases of posttraumatic endophthalmitis, and Aspergillus are the most prevalent fungal cause.[7] The contiguous spread of fungal keratitis is the rarest etiology of fungal endophthalmitis.[8]

Endogenous Endophthalmitis

Endogenous endophthalmitis is rare, compromising only 5%–15% of endophthalmitis. It most often occurs via hematogenous spread secondary to compromised blood–ocular barrier. Patients with endogenous endophthalmitis are primarily immunocompromised or intravenous drug users that develop fungemia. In contrast to other types of endophthalmitis where bacteria are the most prevalent pathogens, the most common cause of endogenous endophthalmitis is fungi. Candida albicans is the leading pathogen for endogenous fungal endophthalmitis. Other Candida species have also been reported, including C. tropicalis, C. glabrata, C. krusei, C. parapsilosis, and C. pelliculosa.[9][10][11] Aspergillus and Fusarium are the most common causative molds.[1][12]

Epidemiology

Endogenous Endophthalmitis

Disseminated Candida infection is the most significant cause of endogenous endophthalmitis. It has been reported that the incidence of endophthalmitis in patients with candidemia ranges from 9% to 40%.[13][14][15][16][17][18] However, recent studies have shown the incidence to be as low as 0 to 2.2%, which could demonstrate that the current practice of prophylaxis and prompt treatment after positive blood cultures has decreased ocular complications of candidemia dramatically.[10][13][19][20][21]

The fungal infection usually seeds the choroid first since it is highly vascular then progresses anteriorly from the outer to inner retinal layers. As a consequence, endogenous fungal endophthalmitis often presents with choroiditis or chorioretinitis then involves the vitreous as the infection worsens. The nature of progression is typically slow.

Risk factors for endogenous fungal endophthalmitis are mainly related to immunosuppression and other factors that increase the colonization or bloodborne infection of Candida. Systemic immunosuppression per se is not sufficient for the development of intraocular candidiasis because it does not increase the access of Candida to the bloodstream. However, in the presence of candidemia, immunosuppression is likely to increase the risk and severity of the ocular infection. Established risk factors for endogenous fungal endophthalmitis include:[22][23]

• Human immunodeficiency virus (HIV) and other immunosuppressive diseases
• Underlying malignancy
• Broad-spectrum antibiotic therapy
• Corticosteroid therapy and other immunosuppressive therapies
• GI trauma or surgery
• Intravenous hyperalimentation
• Indwelling intravenous catheters
• Intravenous drug abuse
• Neutropenia
• Diabetes mellitus
• Renal insufficiency
• Recent hospitalization
• Organ transplant
• Hemodialysis
• Pregnancy, abortion, postpartum state
• Lung disease (specific to Aspergillus)

Two studies found that 90% of patients with endogenous fungal endophthalmitis had one or more underlying medical conditions that predisposed them to the disease.[24][25] However, endogenous fungal endophthalmitis has been seldom reported in immunocompetent patients without underlying predisposing conditions. The disease may be the first manifestation of an occult infection that is focal, so systemic cultures are still negative.[23][25][26][27][28][29][30] It is of note that, despite the very high incidence of mucosal candidiasis, endophthalmitis due to candidemia in patients with HIV infection or acquired immune deficiency syndrome (AIDS) is very uncommon in the absence of other risk factors.[31]

Candida species are the fourth most common cause of nosocomial bloodstream infections, and C. albicans is the most common cause of endogenous fungal endophthalmitis. It is still unknown as to why the eye is a common end-organ target of fungemia. In an experimental study using a rabbit model of C. albicans endophthalmitis, there was evidence to believe that C. albicans had a marked tropism for the eye similar to its tropism for kidneys and endothelium.[22][32]

Neonatal Endophthalmitis

Neonatal endophthalmitis is very rare. Moshfeghi et al. reported a decreasing trend of neonatal endophthalmitis in the United States and determined that the incidence rate was 0.0045% in 2006. Unlike endophthalmitis in adults, neonatal cases are overwhelmingly endogenously sourced with Candida as the most common cause. Retinopathy of prematurity (ROP) is a significant risk factor for and closely associated with neonatal endophthalmitis. It is theorized that fungal infections may cause the release of proinflammatory cytokines that promote retinal neovascularization and progression of ROP. Low birth weight and prolonged hospital stay are also important risk factors.[33][34][35][36]

Exogenous Endophthalmitis

In contrast to endogenous endophthalmitis, exogenous endophthalmitis occurs in otherwise healthy people. Risk factors for exogenous endophthalmitis include intraocular surgery, penetrating trauma, and fungal keratitis. Because of the pathogenesis of exogenous fungal endophthalmitis, the aqueous humor is usually involved first in contrast to endogenous endophthalmitis.[1][22]

Acute-onset postoperative endophthalmitis is rarely fungal,[2] except in tropical regions, such as India, where up to 22% of cases of postoperative endophthalmitis are due to fungi.[3] Chronic postoperative endophthalmitis, a fairly uncommon inflammatory process, is a result of fungal infection in 16% to 27% of cases.[2] Likewise, post-keratoplasty endophthalmitis is rare and occurs in only 0.67% of keratoplasty cases, but up to 33% of cases of post-keratoplasty endophthalmitis are due to fungi.[5] Fungal endophthalmitis following trabeculectomies or intravitreal injections is extremely rare, but there are reported cases due to contamination of the injected compounds.[37][38][39]

Fungal keratitis progresses to endophthalmitis by direct extension of the infection as the fungus invades through the corneal stroma and Descemet’s membrane into the anterior chamber. Contact lens use, trauma with organic matter, and laser-assisted in situ keratomileusis (LASIK) are risk factors for fungal keratitis-derived endophthalmitis. In a retrospective study performed by Henry et al., only 0.5% of eyes with keratitis progressed to culture-proven endophthalmitis. However, fungi accounted for 78% of cases, suggesting that fungal infection may increase the risk of keratitis developing into endophthalmitis. A majority of cases in the study were due to molds, most commonly Fusarium.[8]

History and Physical

Endogenous Endophthalmitis

Patients with endogenous fungal endophthalmitis present with variable clinical signs and symptoms, which can make diagnosis difficult. Patients most commonly present with a subacute onset of decreased vision and floaters that may be associated with a red, painful eye, ocular discomfort, and photophobia. They often have a history of immunosuppression or related aforementioned risk factors. Early or peripheral fungal lesions may be asymptomatic with a patient’s referral for ocular consultation on the basis of positive blood culture or diagnosis of systemic Candida infection.

Physical examination may reveal eyelid edema, conjunctival and circumcorneal congestion, anterior chamber inflammation with or without a hypopyon, absent red reflex, and vitreous exudates and haze. Intraretinal hemorrhages, nerve fiber layer infarcts, Roth spots (Figure 1), and cotton wool spots are nonspecific findings on fundus exam, which can be limited by intraocular inflammation obscuring the view of the fundus.[6][22]

The hallmark for the diagnosis of Candida chorioretinitis is the presence of creamy white lesions at the level of the choroid and retina that is usually associated with vitreous haze. Early lesions are flat in the choroid with no or minimal vitritis. Untreated, they penetrate the blood-retina barrier and extend into the retina and vitreous. At this stage, the lesions become significantly elevated (Figure 2) and are associated with significant vitritis and later heal with scarring (Figure 3) that may result in retinal traction and tractional detachment. The lesions are commonly multiple and can be bilateral in two-thirds of cases.[17] Candida endophthalmitis can also present with vitreal abscesses, which appear as puff ball-like lesions in the vitreous cavity.[6][22]

Aspergillus endophthalmitis presents with yellow-white chorioretinal lesions involving the posterior pole that are often larger, more severe, and more likely to be hemorrhagic. Aspergillus commonly invades the retinal and choroidal vessels, which can lead to ischemic infarcts or full-thickness necrosis of the retina.[39][40]

Exogenous Endophthalmitis

Postoperative fungal endophthalmitis manifests several weeks or months after surgery with symptoms similar to endogenous endophthalmitis.

Posttraumatic fungal endophthalmitis may occur within hours or several weeks after the traumatic injury, particularly with soil, dirty objects, or vegetable matter. Patients present with decreased vision, eye pain out of proportion to exam, edema of the eyelid, corneal ring ulcer, anterior chamber inflammation, hypopyon, vitritis, or frank purulence. The injury may be apparent, and the intraocular inflammation can appear clumped rather than diffuse on the exam. All clinical findings must be evaluated with regard to the degree of injury.

On examination of the cornea in suspected cases of fungal keratitis, the appearance of infiltrates with fuzzy or feathery borders and satellite lesions are highly suggestive of a mold infection. Frond-like projections extending from the back of the cornea into the aqueous or thick clumped material in the aqueous are concerning for the progression of fungal keratitis into endophthalmitis.[1][6]

Evaluation

Diagnosing fungal endophthalmitis requires a thorough history and ophthalmic exam with a high index of suspicion. It is difficult to clinically diagnose fungal endophthalmitis, as there are no pathognomonic signs. Exogenous fungal endophthalmitis warrants inquiries about ocular surgeries or penetrating ocular injuries. For endogenous fungal endophthalmitis, a recent history of infections, surgery, hospitalizations, immunosuppressant use, and intravenous drug use should be noted. A diagnosis of fungal endophthalmitis can be reached by performing the following:

• Ultrasound B-scan is routinely used to evaluate endophthalmitis, especially if the view of the posterior segment is obscured. It is nonspecific but provides information, such as the severity of posterior involvement, the foci of the infection, and the presence of retinal detachment or abscesses, which aid ophthalmologists in formulating appropriate surgical plans.[41]
• Cultures of intraocular fluids aid in the diagnosis of patients with negative blood cultures that present with clinical findings consistent with fungal endophthalmitis. Vitreous cultures are limited by low sensitivity. Tanaka et al. found that only 38% of vitreous specimens in their study generated positive cultures.[42] Vitreous samples can be obtained by needle aspiration or diagnostic vitrectomy, which is more likely to have a higher diagnostic yield, especially if it is performed early.[43] Aqueous samples are also obtained by needle aspiration but have an even lower yield for cultures.[1]
• Blood cultures and complete workup for systemic infection, including echocardiography to look for heart valve vegetations, should be performed for all suspected cases of endogenous endophthalmitis. It is important to note that negative blood cultures cannot exclude endogenous fungal endophthalmitis. In endogenous Candida endophthalmitis, only 50%-75% of patients have positive blood cultures.[44] Cases with negative blood cultures are presumed to be in the setting of transient or intermittent fungemia.[20]
• Every patient diagnosed with systemic fungemia should promptly be referred to an ophthalmologist for a formal ophthalmic exam. If the exam is negative, a repeat exam should be conducted two weeks later.
• Polymerase chain reaction (PCR) has limited clinical use, but several studies have described its diagnostic potential in fungal endophthalmitis and its advantages over cultures. PCR produces rapid results with better specificity and greater sensitivity, as it can identify culture-negative cases without fear of contamination yielding false-positive results.[45][46][47] PCR may also detect fungal DNA in aqueous samples through anterior chamber paracentesis, which is less invasive than vitreous aspiration or biopsy.[48]
• Measuring levels of intraocular fluid beta-D-glucan was described by Chen et al. in 2020 as having a close association with fungal endophthalmitis and being more sensitive than culture methods. It is limited by an inability to confirm specific fungal species.[49]

Treatment / Management

Patients with fungal endophthalmitis should be promptly referred to a uveitis specialist after the disease is suspected or diagnosed. Mild cases that have flat choroidal lesions and minimal retinal or vitreous involvement can be managed with systemic antifungal therapy as the infection is predominantly outside the blood-retina barrier. Moderate or severe cases with raised retinal lesions and more significant involvement of the vitreous are best managed with combined intraocular and systemic antifungal therapies. Early vitrectomy decreases the incidence of late retinal detachment and is recommended in patients with severe vitreous involvement.

Because intraocular Candida infections are commonly part of a systemic infection, systemic antifungal therapy is mandatory. The agents must be able to cross the blood-retina barrier and achieve high ocular concentration, so fluconazole is the preferred agent.[50][51][52] Voriconazole, a second-generation triazole, is another option for primary treatment of endogenous Candida endophthalmitis, particularly in patients with suspected or proven resistance to fluconazole including C. krusei, C. glabrata, and molds infection.[40][43][53] It is of note that while voriconazole has a very extended fungal spectrum, the drug is expensive and requires that drug blood levels are checked periodically to adjust the dose. It is also associated with a higher level of liver toxicity compared to fluconazole. The utility of systemic amphotericin B (AMB) is limited by an inability to penetrate ocular tissues, systemic toxicity, and insufficient activity against non-Candida albicans species and molds.

Intravitreal therapy in fungal endophthalmitis relies on the use of intravitreal AMB or intravitreal voriconazole. While both are effective against fungal endophthalmitis, intravitreal voriconazole is associated with a lower risk of retinal toxicity, has a wider spectrum, and is currently the drug of choice.[40][54] Intravitreal AMB remains a reasonable alternative in eyes with fungal endophthalmitis due to yeast when voriconazole use is not feasible.

The role of vitrectomy surgery to obtain a vitreous biopsy for diagnosis and for the treatment of complications of fungal endophthalmitis, such as persistent vitreous opacities and tractional retinal detachment, is well established. However, the therapeutic benefit of early vitrectomy to control inflammation remains unclear. According to a retrospective study of 44 eyes with endogenous Candida endophthalmitis by Sallam et al., early vitrectomy, within one week of presentation, did not significantly reduce the risk of profound visual loss (postoperative Snellen acuity of ≤ 20/200), yet it decreased the risk of retinal detachment by fivefold.[51] The same results were replicated in a larger retrospective study of 66 eyes that compared eyes undergoing immediate vitrectomy at the time of initial injection of antimicrobial agents to delayed vitrectomy and found no difference in the proportions of eyes reaching a postoperative acuity of ≥20/200.[55]

Differential Diagnosis

Candida chorioretinitis and endophthalmitis should be considered in the differential diagnosis of posterior uveitis or endophthalmitis in a patient who is immunosuppressed, with a recent history of hospitalization or intravenous drug abuse. Important differential diagnoses include:

• Noninfectious uveitis
  • Sarcoidosis
  • Behçet syndrome
  • Sympathetic ophthalmia
  • Juvenile idiopathic arthritis
  • Vogt-Koyanagi-Harada disease
• Infectious chorioretinitis
  • Bacterial endophthalmitis
    • Coagulase-negative staphylococci
    • Staphylococcus aureus
    • Streptococci
    • Tuberculosis 
    • Syphilis
  • Viral endophthalmitis
    • Herpes simplex virus
    • Varicella-zoster virus
    • Epstein-Barr virus
    • Cytomegalovirus
  • Toxoplasma Chorioretinitis 
• Malignancy
  • Intraocular lymphoma
  • Retinoblastoma in children

Prognosis

In general, endogenous fungal endophthalmitis does not have a favorable prognosis and results in complete vision loss, especially if diagnosis and treatment are delayed.[24] Sallam et al. determined that poor visual outcomes, worse initial visual acuity, and centrally located lesion were associated with poor visual outcomes.[51] Virulence of the pathogen is also a significant prognostic factor. Ocular infections by Aspergillus and other molds have a worse visual prognosis than yeasts because they result in more aggressive cases of endophthalmitis.[55][56][57][58]

Complications

While patients with Candida endophthalmitis often achieve a final visual acuity of 6/60 or more,[42][59] patients with candidemia have a high overall mortality rate,[60] which reflects the extent and severity of both the fungal infection and underlying medical problems. Among the etiologies of exogenous fungal endophthalmitis, posttraumatic infections have the worst visual outcomes.[61] Wykoff et al. reported that 70% of eyes with open-globe-associated endophthalmitis required enucleation.[4]

Deterrence and Patient Education

Patients diagnosed with fungal endophthalmitis should be counseled on the importance of medication adherence and the consequences of inadequate treatment. The discomfort of intravitreal injections and the cost of antifungal agents, especially voriconazole, are among the patient factors that inhibit treatment compliance. Patients should be made aware that early and aggressive treatment of fungal endophthalmitis can lead to better outcomes. Otherwise, ocular fungal infections will persist and lead to worsening outcomes.

Enhancing Healthcare Team Outcomes

Interprofessional communication involving healthcare providers from multiple disciplines is key for the coordinated care of patients with fungal endophthalmitis. Consultations with internists or infectious disease specialists should be considered in all cases of fungal endophthalmitis in order to help facilitate the diagnostic workup for systemic fungal infections. Likewise, all cases of fungemia should be referred for ophthalmologic and optometry consultation to rule out ocular involvement. [Level 4][50]

Other specialists that are often involved in the care of patients with fungal endophthalmitis include cardiologists, pulmonologists, and nephrologists. Consultation with cardiologists is required to perform echocardiography to assess for fungal vegetations on heart valves. In cases of Aspergillus endophthalmitis, a pulmonologist will help manage infections of the lungs. Nephrology consultations are necessary when the source of infection is chronic indwelling hemodialysis catheters. Practicing a collaborative and interprofessional team approach will promote improved outcomes for patients with fungal endophthalmitis. Coordinated follow-up with an optometrist working with an ophthalmologist will lead to the best outcomes.