Fungal Endophthalmitis

From EyeWiki


Disease Entity

Fungal endophthalmitis is a rare, purulent fungal infection involving the intraocular fluids (vitreous and aqueous).

Etiology and Risk Factors

The etiology depends on the mode of transmission of the fungus:

Endogenous fungal endophthalmitis

Endogenous endophthalmitis is due to hematogenous ('blood-borne') seeding.  Of all cases of endogenous endophthalmitis including bacterial, over half are due to fungus[1]

Bloodstream seeding secondary to fungus may result from yeast (fungus consisting of single celled organisms) or saprophytic mold (fungus consisting of multicellular filaments called hyphae).

The yeast species candida albicans is the most common fungal microbe implicated in endogenous fungal endophthalmitis [2][3], followed by the mold species aspergillus.

Risk factors for endogenous fungal endophthalmitis

Any cause of fungemia can lead to endogenous endophthalmitis. Risk factors for fungemia include: [4][5][6]

  • IV drug use
  • immunosuppression*
    • corticosteroid use
    • history of solid organ transplant
    • neutropenia
    • diabetes mellitus
    • chemotherapy
  • shock
  • gastrointestinal procedures (especially candida)
  • chronic lung disease (especially disseminated aspergillosis)
  • central venous catheter or other indwelling line
  • hematologic malignancies with or without prior history of stem cell transplantation.
  • prolonged ICU stay
  • mechanical ventilation

*Molds (i.e. aspergillus) have been shown to be significantly associated with immunosuppression and history of organ transplantation when compared to yeast (ie candida). [7][8]

Exogenous endophthalmitis

Among cases of fungal endophthalmitis, exogenous sources are less common. Reported cases have been linked to eye surgery, trauma, or extension of corneal infections. [9] The most common causative organism is aspergillus, in 56-74% of cases, followed by candida, in 11-19% of cases.[10][11]

Following cataract surgery in the United States, the incidence of fungal endophthalmitis has reported to be 0.002% to 0.005%, considerably less than reported incidence of 0.06% for postoperative bacterial endophthalmitis. [12] Risk factors for development of post-cataract surgery fungal endophthalmitis include intraoperative complication and old age. [13]

Prevalence and Incidence

Over half of all cases of infectious endogenous endophthalmitis are due to fungus. [1]

In hospitalized patients with fungemia, the overall incidence of fungal endogenous endophthalmitis remains quite low. Specifically in patients with candidemia, the incidence of chorioretinitis is much higher than that of endophthalmitis. One large study reported a rate of 11% of chorioretinitis while only 1.6% had endophthalmitis. [14]

Endogenous endophthalmitis is frequently unilateral but may progress to bilateral involvement in a quarter to a third a patients.[15] [16]

Pathophysiology

In cases of fungemia, the fungal embolus typically seeds the highly vascular choroid and retina in the posterior pole, acting as a nidus for further dissemination into surrounding ocular structures. [17][18] When the fungal infection is limited to the choroid and retina alone, these lesions are defined as fungal chorioretinitis as opposed to endophthalmitis, given the lack of vitreous involvement. During this stage, patients may remain asymptomatic.

As the fungal chorioretinal lesions progress, the infectious infiltrates may then lead to compromise of the blood-ocular barrier, resulting in endophthalmitis.

In cases of exogenous post-operative fungal endophthalmitis, previous studies have shown candida, aspergillus and, fusarium are ubiquitous airborne contaminants found on the human conjunctiva, especially in warmer climates. [19][20] It may be extrapolated that introduction of fungal contaminant via the conjunctival surface or surgical equipment may play a role in pathogenesis.

Diagnosis

Fungal endophthalmitis is a clinical diagnosis based on exam findings including the presence of vitreous inflammation in the setting of epidemiologic risk factors. The diagnosis is confirmed by microbiology cultures.

Blood Cultures

Blood cultures have reported to be positive in only one third to one half of confirmed cases of endogenous fungal endophthalmitis. [21][16][22] This may be partially explained by the difficulty in culturing from blood samples and the transient nature of fungemia, whereby the systemic infection may be missed at the time the eye is seeded.

Microbiology

Aqueous or vitreous samples are helpful in confirming the diagnosis and assessing for antimicrobial susceptibilities. Posterior chamber paracentesis is more reliable and sensitive than aqueous samples.[23] Furthermore, undilute samples from vitrectomy have even higher diagnostic yield than posterior chamber paracentesis.[24]

Although culture of intraocular fluids is gold standard, it has poor sensitivity and slow rate of growth. PCR of common organisms (ie candida, fusarium, aspergillus) has emerged as a relatively rapid method of identifying fungal species, even in culture negative samples.[16]

Symptoms

  • Floaters
  • Vision loss
  • Eye pain
  • Eye redness
  • Fever (if fungemic)
  • Systemic symptoms due to liver or lung involvement (if disseminated aspergillosis)

Symptoms of endogenous aspergillus endophthalmitis tend to be more acute with relatively rapid progression of severe vision loss due to large area of macular involvement and dense vitritis.[25] In contrast, symptoms of endogenous candidal endophthalmitis are generally more insidious, with vision loss occurring over a period of days to weeks with minimal pain until later in the progression of the disease.[26]

Symptoms of exogenous fungal endophthalmitis often present as a sub-acute to chronic endophthalmitis. There is a wide range of latency with onset of symptoms occurring several weeks to months following the initial inoculation, depending on the burden of implicated fungus. [27][28][29]

Physical Exam Findings

In endogenous fungal endophthalmitis, dilated exam reveals yellowish fluffy chorioretinal infiltrates with ill-defined, irregular borders predominantly involving the posterior pole associated with varying degrees of vitritis. Vitritis must be present to make the diagnosis of fungal endophthalmitis. In the absence of vitritis, fungal chorioretinitis is a more fitting diagnosis. Intraretinal hemorrhages may also be present.

When comparing clinical manifestations of differing fungal organisms in endogenous sources, there are a couple of notable differences:

  • Classically candidal endophthalmitis presents with slowly progressive focal vitritis overlying chorioretinal lesions. These discrete areas of vitritis may present with consolidated fungal abscess balls adjacent to one another in a "string of pearls" configuration.
  • Aspergillosis tends to have more rapidly progressive, large macular lesions
  • Aspergillosis tends to be more hemorrhagic due to angiocentric invasion of the mold hyphae. This invasion leads to retinal and choroidal vessels causing retinal vessel occlusion and choroidal ischemia

Exogenous fungal endophthalmitis predominantly presents with vitritis that may be focal or diffuse. [30]

Imaging

OCT

In candidal endophthalmitis, OCT imaging of retinal lesions have demonstrated involvement of all layers of the retina (pre-retinal, subretinal, intraretinal, full-thickness)[31].

Alternatively, aspergillus endophthalmitis classically preferentially demonstrates subretinal involvement with relatively normal overlying retinal architecture. [32]

B-Scan

Signs of endophthalmitis on b-scan include vitritis as well as chorioretinal thickening.   

Choroidal or retinal detachments can also occur, both of which are poor prognostic factors.  

Differential Diagnosis

  • bacterial endophthalmitis
  • acute retinal necrosis
  • toxoplasmosis chorioretinitis
  • retinoblastoma
  • intraocular lymphoma
  • leukemic infiltrate
  • Sarcoidosis
  • Behcets
  • VKH
  • Tuberculosis

Management

Medical Therapy

Medical therapy for fungal endophthalmitis can be administered systemically and/or intravitreally depending on the severity of intraocular involvement. Intravitreal therapy should be considered in patients with vitritis or endophthalmitis, chorioretinitis involving the macula, or any patient persistently worsening on systemic therapy alone.  

There are four classes of medications used to treat disseminated fungal infections today, however, not all have equal effect in treating intraocular fungal infections. Amphotericin B was the first anti-fungal medication to be developed in the 1950s and belongs class of antifungals known as polyenes. While Amphotericin B has broad-spectrum coverage, it has limited intraocular penetrance when used systemically, as well as numerous risks and side effects such as infusion reactions, electrolyte abnormalities, and renal failure. [33] The preferred method of drug delivery for Amphotericin B in these cases is intravitreal, though there is a potential risk of retinal toxicity and necrosis in high doses.[34]

The first generation of triazoles, which includes fluconazole, demonstrate excellent activity against Candida species however does not cover invasive filamentous fungal infections such as aspergillosis or mucormycosis. Systemic fluconazole is generally well tolerated and has superior intraocular penetrance compared to most other antifungals. Voriconazole is a second generation triazole and has added activity against filamentous fungi compared to first generation triazoles as well as fluconazole-resistant Candida species such as Candida glabrata and Candida krusei. Like fluconazole, it also has excellent intraocular penetrance. [33] Voriconazole can also be given as an intravitreal injection and may be safer than amphotericin B given the lack of demonstrated dose-dependent toxicity in animal studies. [35]

Ultimately, diagnosis of endogenous endophthalmitis warrants a systemic workup and assistance from infectious disease specialists. Per the most recent IDSA guidelines, echinocandin is often started as the initial therapy in candidemia. [36] However, it is important to note that the ocular penetrance of echinocandin is poor, and in instances of endogenous intraocular candidiasis, an alternative systemic therapy such as an azole should be recommended to the primary treating team. [37]

The length of treatment with systemic anti-fungal therapy is typically 4-6 weeks, with the final duration depending on treatment response as well as presence of other organ involvement. Serial exams should be performed on patients to assess treatment response. [36]

Surgical Therapy

There is no current consensus regarding the role of surgery, such as pars plana vitrectomy (PPV), in treating fungal endophthalmitis. Because the Endophthalmitis Vitrectomy Study (EVS) did not enroll patients with endogenous endophthalmitis, it cannot be directly applied to patients with endogenous endophthalmitis for fungi. However, there has been evidence of the benefit of performing a PPV to aid in both diagnosis and treatment of endogenous fungal endophthalmitis. [38]Though the treatment benefit may not necessarily be reflected in final visual acuity, instead PPV may hasten time to recovery and reduce risk of retinal detachment. [39]

Complications

Complications from fungal endophthalmitis are largely secondary to the intraocular inflammation they cause. They can include retinal detachments, chorioretinal scarring, epiretinal membrane, cataract formation, and persistent vitreous opacification.  [40]

Prognosis

The prognosis for fungal endophthalmitis, as with other forms of infectious endophthalmitis, is generally poor. Though outcome can vary depending on location of lesions and virulence of fungus. Factors associated with a poorer prognosis include delay in treatment, traumatic etiology of infection, and infection with Aspergillus species. 

Follow-up

Follow up patterns vary by institution, as there is no clearly defined protocol. At the authors' institution, for non-verbal (i.e. intubated) fungemic patients with a normal initial dilated fundus exam, a repeat dilated fundoscopic exam is performed two weeks after the initial exam due to the slowly progressive nature of fungal endophthalmitis and proportion of cases that can be missed on initial evaluation (13% by one study). [41] In contrast, patients that are asymptomatic at presentation with a normal eye exam and remain asymptomatic may be followed on an as-needed basis.  

If abnormal findings are present on the initial exam, a repeat exam should be done in one week or sooner if new visual symptoms should develop, to assess for evolution.  

In patients who have confirmed fungal endophthalmitis, depending on intervention (PPV, intravitreal injection, systemic antifungal therapy) close observation is often appropriate for the initial several days to assess response to treatment. Exams can later be spaced out once exam has been shown to have documented improvement. 

References

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