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Aspergillus endophthalmitis

Several species of Aspergillus, particularly  Aspergillus fumigatus and Aspergillus flavus,  may cause endophthalmitis which is defined as intraocular inflammation involving the vitreous and anterior chamber. Exogenous Aspergillus endophthalmitis may follow ocular surgery, trauma to the eye or extension from Aspergillus keratitis while endogenous Aspergillus endophthalmitis may arise due to intravenous drug abuse, immunosuppression associated with organ transplants, valvular cardiac surgery, haematological malignancies and a human immunodeficiency virus-positive status.

Intraocular fungal infection usually develops slowly, spreads to the eye through the blood stream, and consists of focal or multifocal lesions in the choroid and retina (chorioretinitis). The intensity of inflammation of the anterior segment of the eye varies from mild to severe, the severe variety resulting in the formation of an hypopyon (Weinberg, 1999). When the initial focus of intraocular fungal infection in the choroid and retina extends into the vitreous to produce inflammation, which may involve the entire internal structure of the eye, endophthalmitis results. It is difficult to separate fungal retinitis from fungal endophthalmitis (Hamza et al. 1999). 

Endophthalmitis can be divided into

• endogenous endophthalmitis, which arises from haematogenous spread from a focus of infection elsewhere in the body, and
• exogenous endophthalmitis, resulting from primary inoculation of the eye following surgery or penetrating trauma.
  
  The first case of exogenous Aspergillus endophthalmitis was reported in 1898 in Heidelberg (Nobbe), whereas endogenous endophthalmitis was recognized only in 1975, in two renal transplant recipients (Naidoff and Green). At least 14 reports of this condition appeared in the world literature between 1913 and 1971 (Dimmer 1913; Stock 1926; Archangelsky 1928; Lorenz 1933; Rohner & Huber, 1933; Cogan 1949; Harley & Mishler, 1959; Paradis & Roberts, 1963; Lemmingson & Vogel, 1964; Danis et al., 1966; Lederman & Madge, 1966; Darrell 1967; Sugar et al. 1967; Walinder & Kock, 1971).

Aspergillus species are less frequent causes of exogenous or endogenous endophthalmitis than Candida spp, except in the context of an outbreak (Tabbara and al-Jabarti, 1998; Gupta et al. 2000) or post-operatively (Narang et al,  2001). Numerous species of Aspergillus may be involved including A. flavus, A. fumigatus, A. niger, A. terreus, A.  ustus and A. versicolor.

Risk factors 

Endogenous Aspergillus endophthamitis is most commonly reported in immunosuppressed patients especially those who have undergone solid organ transplants (Hashemi et al., 2009; Hosseini et al. 2009) or after valve replacement (Darrell, 1967; Del Pozo et al., 2009; Gregory et al., 2009). In a retrospective analysis of clinical and histopathological features in 13 patients with morphologic features and/or positive culture for Aspergillus who had undergone enucleation, 12 of the 13 patients had received immunosuppressive agents or had undergone  organ transplants or valvular cardiac surgery; in contrast, in 12 patients with histologic evidence and/or positive cultures for Candida,  a similar clinical history was present in only one (Rao & Hidayat, 2001).

Intravenous drug abusers are also prone to develop endogenous fungal endophthalmitis, probably because of contaminated drugs and injection gear (Sugar et al., 1971). Schelenz & Goldsmith (2003) in a review of renal transplant recipients with Aspergillus endophthalmitis identified possible risk factors as cytomegalovirus infection, diabetes mellitus  and treatment for rejection. Endogenous Aspergillus endophthalmitis has also been reported in individuals suffering from haematological malignancies (Danis et al., 1966).

Risk factors for exogenous endophthalmitis due to Aspergillus species include ocular (usually cataract) surgery and ocular trauma.

Clinical features
Symptoms of fungal endophthalmitis include:

visual loss,
the presence of a red eye,
photophobia,
pain and floaters

Some patients are asymptomatic if the lesion is in the peripheral retina or if the patient is moribund. Endogenous Aspergillus endophthalmitis presents more acutely (mean duration of 5 days) compared with Candida endophthalmitis (the mean duration from onset of symptoms to initial treatment being 61 days). Aspergillus endophthalmitis may present with distinctive signs including an iridocyclitis (with or without an hypopyon), yellow subretinal and retinal infiltrates that preferentially affect the macula, inflammatory cells within the infiltrate (Peyman et al, 2004) and/or an inferior gravitational layering of inflammatory exudate in either or both the subhyaloid and subretinal space (Weishaar et al, 1998). As the disease progresses, the vitreous becomes markedly involved, obscuring the fundus. Over time, scarring of the macula occurs. If the fungus invades the choroidal vessels, an exudative retinal detachment occurs; when the retinal vessels become involved, retinal necrosis may occur (Peyman et al, 2004). When data pertaining to 27 patients with exogenous fungal endophthalmitis (20 due to Aspergillus species) were evaluated, substantial corneal involvement was noted in 14 eyes, which multivariate analysis revealed was the single most important risk factor in determining final visual outcome (Narang et al, 2001). Superior limbal, scleral and corneal infiltration may occur in exogenous endophthalmitis  following cataract surgery (Tabbara & al-Jabarti,  1998).

Endogenous Aspergillus endophthalmitis may be the presenting feature of disseminated aspergillosis (Peyman et al, 2004). Hence the occurrence of endophthalmitis in a patient with symptoms and signs (e.g. pulmonary lesions) of disseminated aspergillosis should alert the clinician to a possible diagnosis of endogenous Aspergillus endophthalmitis. However, there are other features that should be looked for. A characteristic acute onset of  intraocular inflammation, with a one or two day history of pain and marked loss of visual acuity, vitritis and, frequently, a chorioretinal lesion located in the macula, have been noted in patients with culture-proven endogenous endophthalmitis due to Aspergillus species (Weishaar et al, 1998).. All the eyes with Aspergillus infection had a poor visual outcome (worse than 20/400) due to direct infection of the macula or persistent retinal detachment (Essman et al. 1997; Schiedler et al. 2004; Leibovitch et al. 2005;  Ness et al. 2007). 

Diagnosis

Since anterior chamber and /or vitreous inflammation may obscure visualization of the retina, echography may help to determine the anatomic status of the retina, the extent of inflammation, the presence of choroidal detachment, and the presence and location of intraocular foreign bodies.

Fungal chorioretinitis and endogenous fungal endophthalmitis are exceptions to the rule requiring isolation of a fungal strain from an ocular sample to confirm the diagnosis of an ocular fungal infection (Thomas, 2003); however, if non-specific findings are present, or if there is no positive culture from an extraocular site, a diagnostic vitrectomy can be performed. The diagnosis of exogenous fungal endophthalmitis is ultimately established by demonstrating fungi in samples from the vitreous or aqueous.

Samples of aqueous and vitreous should be obtained prior to instituting therapy. A vitrectomy specimen (where much of the vitreous is cut and removed by a vitreous cutter) is preferable to a vitreous aspirate (vitreous tap) sample (where only the putative focus of infection is sampled) since the latter may fail to sample the actual locus of infection. Although culture of an anterior chamber aspirate is a poor diagnostic technique and culture of a vitreous sample is more likely to yield positive results (Gupta et al, 2008), both samples should be obtained whenever possible. A conjunctival swab is of relevance only if there is a leaking filtering bleb.

Fungal endophthalmitis can be confirmed by direct microscopic demonstration of fungal hyphae or yeast cells in 10% KOH wet mounts, or smears stained by calcofluor white and the Gram method (Brar et al, 2002). Culture is performed on fungal and bacterial media, the best results being obtained if direct inoculation of vitreous and aqueous samples on the culture media is done immediately after collection. To facilitate recovery of fungi, vitrectomy samples can be concentrated by centrifugation or cellulose membrane filtration prior to inoculation onto culture media (Peyman et al, 2004).  

Endophthalmitis due to Aspergillus species is comparatively more difficult to diagnose than that due to Candida species since skin and serological tests are unreliable, pulmonary radiographic studies and echocardiograms may yield little information, blood cultures are almost always negative (even in patients with disseminated disease) and systemic manifestations are often lacking in intravenous drug abusers infected with Aspergillus (Lance et al, 1988; Weishaar et al, 1998, Peyman et al, 2004). A diagnostic vitreous aspirate for cytology and culture isolation is usually necessary to identify this aetiological agent (Lance et al,1988). However, diagnosis of endogenous Aspergillus endophthalmitis by anterior chamber or vitreous aspirates / biopsies alone may be unreliable, since aspergillosis clinically presents with extensive areas of deep retinitis/choroiditis (Rao & Hidayat,  2001). Culture of pars plana vitrectomy specimens, in conjunction with examination of Gram- or Giemsa-stained smears, appear to yield the highest percentage of positive results (almost 90% for previously untreated eyes) for Aspergillus (Weishaar et al,1998). A review of the literature on endogenous Aspergillus endophthalmitis occurring in patients who had undergone renal transplantation revealed that in 70% of the patients, histology, microscopy or culture of vitreous fluid confirmed the diagnosis (Schelenz & Goldsmith, 2003).

In recent years, the value of DNA-based technology in the diagnosis of fungal endophthalmitis has been evaluated (Bagyalakshmi et al. 2007), but there are few reports on the use of such technology specifically for the diagnosis of Aspergillus endophthalmitis. In one study on 27 intraocular specimens from 22 patients with suspected fungal (non-bacterial) endophthalmitis, four were positive for Aspergillus species by both culture and the polymerase chain reaction (PCR) and two were positive for Aspergillus species by PCR but negative by culture; PCR yielded results in just 24 hours whereas isolation and identification of  Aspergillus by conventional culture methods took an average of 10 days (Anand et al, 2001). Biswas et al. (2008) described the diagnosis of A. fumigatus endophthalmitis from formalin-fixed paraffin-embedded tissue by PCR-based restriction fragment length polymorphism. This was done by applying the technique to the paraffin section of an eyeball that had been enucleated from an eight-month-old child due to endogenous endophthalmitis. Very recently, Sowmya & Madhavan (2009) observed that PCR on intraocular specimens is a specific and several-fold more sensitive etiologic diagnostic tool than cultures, leading them to conclude that PCR may be considered the gold standard to establish the etiology of infectious endophthalmitis; they also opined that as there was no statistically significant difference in the results of PCR on samples of aqueous and vitreous, PCR on samples of aqueous could be the method of choice considering safety and simplicity of the procedure of its collection.

Histopathological studies have provided useful information about the extent and pathogenesis of Aspergillus endophthalmitis (Wollensak & Green 1999; Rao & Hidayat 2001).  The subretinal space or sub-retinal pigment epithelium appears to be the primary focus of infection in endogenous Aspergillus endophthalmitis, in contrast to endogenous Candida endophthalmitis where the vitreous appears to be the primary focus (Rao & Hidayat, 2001). This may explain why vitreous biopsy may not yield positive results in Aspergillus endophthalmitis. Another important finding in Aspergillus endophthalmitis, and not in Candida endophthalmitis, is the occurrence of invasion of retinal and choroidal vessel walls by fungal elements (Rao & Hidayat, 2001). In one ultrastructural study of endogenous Aspergillus endophthalmitis (Wollensak & Green 1999), the spread of A. fumigatus along two separate paths, that is via the retinal and choroidal vessels, resulted in separate, non-contiguous lesions; moreover, while the fungi were found to have penetrated the blood vessel walls, Bruch's membrane and the internal limiting membrane, the retinal pigment epithelial layer was spared. Interestingly, the retinal pigment epithelium appeared to act as a barrier, since the subretinal space was not invaded; however, phagocytosis of fungi by the retinal pigment epithelium was observed (Wollensak & Green 1999).    The severity of retinal involvement in endogenous Aspergillus endophthalmitis may range from subretinal or subhyaloid infiltrates to vascular occlusion and full-thickness retinal necrosis; intraretinal hemorrhages are frequent (Peyman et al, 2004). Interestingly, histopathological examination of an eye with severe Aspergillus endophthalmitis that had been enucleated while the patient was receiving oral treatment with voriconazole revealed no fungal elements in choroidal or retinal vessels, the fungal hyphae mainly being restricted to the vitreal side of the preretinal inflammatory infiltrate without retinal vessel involvement (Aliyeva et al, 2004). This suggests promising activity and ocular penetration of voriconazole for this indication.

Treatment

Vitrectomy is generally advised for the treatment of fungal endophthalmitis in all but very mild or exceptional cases, for example where the condition of the cornea does not allow this (Narang et al, 2001; Shen and Xu, 2009). Vitrectomy removes the bulk of inflammatory debris and microorganisms. Vitrectomy allows:

• acquisition of a large sample for laboratory study;  

• concentration of the sample by centrifugation or filtration to give a better yield from culture;

• debulking of inflammatory and infectious material from the vitreous; removal of the scaffolding for vitreoretinal traction bands and epiretinal membranes that can contribute to late-developing macular pucker and retinal detachment;

• direct injection of antifungals into the vitreous cavity (Peyman et al, 2004).

  The indications for vitrectomy in patients with fungal chorioretinitis and endophthalmitis are advanced cases with extensive vitreous involvement and poor response to systemic antifungal therapy (Peyman et al, 2004; Gonzalez-Granado 2009; Shen and Xu, 2009).

 
 In the case of exogenous endophthalmitis, surgical measures include excision of clinically involved tissue, vitrectomy (if there is visible vitreous involvement) and  retention of the intraocular lens (if the endophthalmitis is a sequel to cataract surgery),  unless there is extensive infiltration around the lens or recurrent infection. If endophthlamitis is a consequence of extension from keratitis, surgery is indicated if there is deep keratitis with retrocorneal or anterior chamber involvement unresponsive to medical therapy. Surgical approaches include penetrating keratoplasty with retention of the iris and lens (if possible), or iridectomy, lensectomy and vitrectomy if there is clinical evidence of infiltration of these structures, or if there is recurrence of the endophthalmitis. Vitrectomy and intravitreal injections are better avoided in cases of neonatal endophthalmitis.

In addition to vitrectomy, antifungal agents may be administered orally, parenterally and by intravitreal or intracameral injection. Amphotericin B, the most widely used systemic agent in treatment of Aspergillus endophthalmitis, achieves relatively low concentrations in the aqueous and vitreous when used intravenously, hence intravitreal administration of amphotericin B is done at the time of vitrectomy. Amphotericin B deoxycholate (5 to 10 µg) is injected in regions of maximal involvement (these injections may be repeated if indicated). In the local treatment of endogenous fungal endophthalmitis. periocular amphotericin B is rarely used because it has poor intravitreal penetration and frequently causes marked conjunctival necrosis. Intravenous amphotericin B is recommended for advanced endogenous fungal endophthalmitis, particularly if other non-ocular sites are involved (Weishaar et al,1998; Flynn, 2001), although there is uncertainty about its intraocular penetration, especially if administered as a lipid preparation. An improvement in visual acuity together with a reduction of vitreous inflammation in endogenous endophthalmitis due to A. versicolor following administration of intravenous (IV) liposomal amphotericin B has been described (Perri et al. 2005); similarly, a patient with exogenous (post-operative) A. flavus endophthalmitis was treated successfully with topical amphotericin B, IV liposomal amphotericin-B and caspofungin following vitrectomy (Aydin et al., 2007). . Less toxic triazole compounds (itraconazole, voriconazole and posaconazole) can supplement intravitreal therapy and may contribute to a favourable clinical response without the risk of unwanted side-effects. Because of its broad spectrum of coverage, low MIC90 levels for Aspergillus spp., good tolerability, and excellent bioavailability with oral administration, voriconazole has recently emerged as a major advance in the management of exogenous or endogenous fungal endophthalmitis (Hariprasad et al, 2004; Vasconcelos-Santos and Nehemy, 2009). Very recently, appropriate voriconazole concentrations following oral administration of the drug were observed in the serum and vitreous samples of an immunocompetent patient with endogenous Aspergillus endophthalmitis (Logan et al., 2010). Voriconazole may also be given intravitreally but the optimal dose of voriconazole for intravitreal administration in Aspergillus endophthalmtis has not been defined. In an experimental study, intravitreal administration of voriconazole up to 25 µg /mL did not cause any change in the electroretinogram or histologic abnormality in rat retina (Gao et al., 2003). A patient with post-traumatic endophthalmitis due to Scedosporium apiospermum was successfully treated with an intravitreal dose (200 µg) of voriconazole along with systemic voriconazole (Zarkovic et al., 2007) while, more recently, a patient with Candida endophthalmitis was treated with intravitreal voriconazole (80 µg / 0.1 ml). Topical administration of 1% voriconazole every 2 hours for 24 hours has been reported to yield mean (SD) voriconazole concentrations in the aqueous and vitreous of 6.49 (3.04) µg/mL and 0.16 (0.08) µg/mL, respectively, in the non-inflamed human eye; the aqueous concentrations are therapeutic for many fungi and moulds while the vitreous concentrations are therapeutic for Candida species (Vemulakonda et al, 2008).  

Alternatives for intravitreal antifungal therapy include miconazole (25 to 50 µg) administered with topical therapy administered hourly. i.e. topical miconazole (1%) and subconjunctival  miconazole (5 to 10 mg).

The role of intravitreal corticosteroids remains controversial, but can be considered if appropriate antimicrobial coverage of the causative organism can be assured (Flynn, 2001). Intravitreal dexamethasone (400 mg) has been used with antifungal therapy to reduce the marked intraocular inflammation in many of these eyes, but it is unclear if it is of benefit.  

Outcome

The outcome of treatment of Aspergillus endophthalmitis is highly variable, ranging from death of the patient due to disseminated aspergillosis (Augsten et al, 1998; Rao & Hidayat, 2001; Leibovitch et al, 2005) to enucleation or evisceration of the affected eye (Rao & Hidayat, 2001; Machado et al, 2003; Aliyeva et al, 2004; Callanan et al, 2006; Fajardo Olivares et al, 2006; Yildiran et al, 2006; Moinfar et al, 2007;  Saracli et al, 2007; Pollack et al, 2008) to poor outcome (Schiedler et al, 2004) to improvement in the clinical condition (Durand et al, 2005; Perri et al, 2005; Callanan et al, 2006; Kramer et al, 2006;  Aydin et al, 2007; Bifrare & Wolfsenberger, 2007; Bakri et al., 2010). Immunocompromised individuals with endophthalmitis had a mortality ranging from 70 to 100% before the millennium, but a combination of vitrectomy and intravitreal amphotericin B appears to be the best way to manage such patients (Schelenz & Goldsmith 2003). The combination of pars plana vitrectomy, intravitreal amphotericin B (5-10 mg) (repeated in some patients), intravenous amphotericin B and intravitreal  dexamethasone 400 mg resulted (in 12 eyes of 10 patients with endogenous Aspergillus endophthalmitis) in a significant improvement in visual acuity in three eyes without central macular involvement and an improvement in visual acuity in eight eyes with initial central macular involvement, while two eyes had to be enucleated due to intense pain and associated complications (Weishaar et al.1998). Further improvements may be seen with voriconazole therapy.

The outcome of treatment of post-operative Aspergillus endophthalmitis is also varied, with successful outcomes being been reported by a few investigators (Das et al. 1993;  Durand et al. 2005; Aydin et al. 2007) and treatment failures by others (Oxford et al. 1995; Tabbara & al-Jabarti  1998; Yildiran et al. 2006; Saracli et al. 2007).

Infections with resistant pathogens, such as A. terreus and A. ustus (now A. calidoustus) generally do poorly with amphotericin B therapy, and voriconazole is preferred.

Philip A. Thomas, MD, PhD
Professor and Head
Department of Microbiology
Institute of Ophthalmology
Joseph Eye Hospital, P.B. 138
Tiruchirapalli, 620001
India.

Telephone: +91-431-2460622
Telefax: +91-431-2414969

e-mail: philipthomas@sify.com; philipthomas@satyam.net.in

March 2010