Chapter 171 – Candidiasis, Aspergillosis, and Coccidioidomycosis
RAMANA S. MOORTHY
• A chronic intraocular inflammation induced by fungi such as Candida albicans, Coccidioides immitis, and Aspergillus spp.
• Candidal intraocular infection usually manifests as a fluffy white choroidal or retinal lesion with white snowball-like vitreous opacities.
• Aspergillus causes endophthalmitis via hematogenous spread, usually from the lung.
• Coccidioidal intraocular inflammation may appear as chronic iridocyclitis, iris granuloma, choroiditis, or chorioretinitis.
Candidal Intraocular Infection
• Usually seen in immunocompromised individuals, presence of candidemia.
Aspergillus Endogenous Endophthalmitis
• Usually seen in immunocompromised individuals but rarely in healthy patients.
Coccidioidal Intraocular Inflammation
• Systemic coccidioidal infection, endemic in American Southwest, including the San Joaquin Valley in California, northern Mexico, and Argentina.
Various fungi can cause chronic granulomatous or nongranulomatous uveitis or other intraocular inflammations. The infectious agent can gain access into the ocular cavity either by traumatic introduction (exogenous) or through hematogenous spread (endogenous). In this chapter clinically significant and varied endogenous fungal intraocular inflammation caused by Candida albicans, Coccidioides immitis, Aspergillus flavus, and Aspergillus fumigatus are discussed. The exogenous infections are discussed in Chapter 169 .
CANDIDA ALBICANS—ENDOGENOUS ENDOPHTHALMITIS
Candida albicans is an important nosocomial, diphasic fungal pathogen. The yeast form is responsible for human disease. The incidence of hospital-acquired candidemia appears to be increasing as the number of immunocompromised patients rises.
EPIDEMIOLOGY AND PATHOGENESIS
Patients who develop endogenous candida endophthalmitis are usually immunocompromised. Most patients either have a chronic underlying systemic illness, an associated septicemia for which broad spectrum systemic antibiotic therapy is being administered, intravenous hyperalimentation with chronic indwelling catheters, or an organ transplantation that requires immunosuppression.  In addition, intravenous drug abusers and those with acquired immunodeficiency syndrome are also at high risk for candida endophthalmitis.
Patients who have endogenous candida endophthalmitis seek treatment for ocular pain, decreased vision, and floaters. The typical lesion of candida endophthalmitis is that of a white, fluffy, chorioretinal lesion that has overlying vitreous inflammation and haze ( Fig. 171-1 ). The infection can extend into the vitreous and produce white snowball-like opacities. The retinochoroiditis may progress and satellite lesions may develop adjacent to the primary lesion. Occasionally anterior uveitis, scleritis, or panophthalmitis also may occur.
Diagnosis usually is based on the typical clinical appearance. Cultures of blood, catheter tips, surgical wounds, and body fluids are often positive for Candida. Diagnostic vitreous biopsy and cultures may be required to confirm the diagnosis. Polymerase chain reaction (PCR)–mediated detection of C. albicans in vitreous has been performed successfully and may be used to aid in the diagnosis.
The differential diagnosis of candida endophthalmitis is given in Box 171-1 .
Candidal fungemia can lead to the development of random lesions in the eye, particularly in the vitreous, retina, and choroid.
Figure 171-1 Fifty-year-old patient with endogenous candida endophthalmitis with a history of pancreaticoduodenectomy requiring intravenous hyperalimentation. Note vitreous haze from vitreitis, white chorioretinitis over the optic disc, and a separate focus in macula of the right eye.
Differential Diagnosis of Candida Endophthalmitis
Endogenous bacterial endophthalmitis
Primary intraocular lymphoma
The lesions demonstrate polymorphonuclear leukocytes, lymphocytes, budding yeast, and pseudohyphae. Choroidal and retinal vessel wall invasion is not seen in candida endophthalmitis. The vitreous is the primary focus of infection in candida endophthalmitis. The vitreous inflammatory masses also may contain the organism.
Because most patients with candida endophthalmitis have concurrent candida septicemia, intravenous amphotericin B therapy is recommended. A total intravenous dose of 1?g usually is sufficient to eradicate endogenous candida endophthalmitis when given over a 4–6 week period. 5-Fluorocytosine may be substituted for or given concurrently with amphotericin B in particularly resistant cases.
Persistent candida endophthalmitis that does not respond to systemic intravenous amphotericin B should be treated with pars plana vitrectomy (PPV) and an intravitreal injection of 5?µg of amphotericin B. PPV has now become an essential part of the management of most cases of candida endophthalmitis, especially those with marked vitreous infiltration.
Nephrotoxicity is the most serious complication of systemic amphotericin B therapy. Consultation with an infectious disease specialist and careful monitoring of serum creatinine levels are recommended for patients who receive intravenous amphotericin B.
COURSE AND OUTCOME
Rapid diagnosis and induction of systemic amphotericin B therapy are essential for both reduction of mortality and ocular morbidity
Figure 171-2 Twenty-seven-year-old patient with endogenous aspergillus endophthalmitis. Fundus photograph demonstrates a posterior hyaloidal hypopyon and a chorioretinitis affecting the macular region.
associated with endogenous candida endophthalmitis. Efficacy of treatment is determined by close ophthalmic follow-up. The patient may need to be examined twice weekly for the first 2 weeks, followed by weekly bilateral dilated fundus examinations. Often, significant visual improvements occur within 1 week of initiating systemic amphotericin B therapy. The visual prognosis for candida endophthalmitis is better than for that caused by Aspergillus if properly managed. Approximately 76% of eyes in one series achieved a final visual acuity of 20/400 or better.
ASPERGILLUS FLAVUS AND FUMIGATUS—ENDOGENOUS ENDOPHTHALMITIS
EPIDEMIOLOGY AND PATHOGENESIS
Aspergillus fumigatus is the most common pathogen in human aspergillosis, followed by A. flavus, A. niger, A. nidulans, and A. terreus. Endogenous aspergillus endophthalmitis is a rare disorder associated with disseminated aspergillosis and intravenous drug abuse.  Disseminated aspergillosis appears to be most common among patients with severe chronic pulmonary diseases or those who are severely immunocompromised. It has been reported in particular among patients following orthotopic liver transplantation.  The eyes are a common site of infection, in some series second only to the lung. Rarely aspergillus endophthalmitis may occur in immunocompetent patients with no apparent predisposing factors.
Aspergillus spp. commonly grow in soils and decaying vegetation. They are ubiquitous saprophytic spore-forming molds. The spores or conidia become airborne and seed the lungs and paranasal sinuses of humans. Although exposure is very common, human infection is rare. Predisposing conditions of the host combined with virulence of Aspergillus spp. affect development of human disease. Hematogenous dissemination of organisms from the lung to the choroid results in ocular disease. 
Endogenous aspergillus endophthalmitis has characteristic ocular features. Patients develop rapid onset of pain and visual loss. A confluent yellowish infiltrate is seen in the macula beginning
Figure 171-3 Light micrograph of vitreous aspirate demonstrating large branching septate hyphae of Aspergillus fumigatus. Periodic acid-Schiff, ×520.
Differential Diagnosis of Endogenous Aspergillus Endophthalmitis
• Candida endophthalmitis
• Cytomegalovirus retinitis
• Toxoplasma retinochoroiditis
• Coccidioidomycotic choroiditis/endophthalmitis
• Bacterial endophthalmitis
in the choroid and subretinal space. A hypopyon develops in the subretinal or subhyaloidal space ( Fig. 171-2 ). This can progress to retinal vascular occlusion and full-thickness retinal necrosis. Intraretinal hemorrhages usually occur. Eventually the infection spreads into the vitreous, producing dense vitritis and into the anterior segment, producing varying degrees of cell, flare, and hypopyon in the anterior chamber. The macular lesions heal to form a central atrophic scar.
The diagnosis of endogenous aspergillus endophthalmitis is based on pars plana vitreous biopsy and cultures aided by Gram and Giemsa stains ( Fig. 171-3 ).  Anterior chamber and vitreous aspirates alone are unreliable. Coexisting systemic aspergillosis may provide obvious clues to the clinical diagnosis, especially among high-risk patients.
The differential diagnosis of endogenous aspergillus endophthalmitis is given in Box 171-2 .
Aspergillus endophthalmitis lesions have a predilection for the postequatorial fundus.  Histologically, these retinal and choroidal lesions are angiocentric. Extensive areas of deep choroiditis and retinitis may be present. Mixed acute (polymorphonuclear leukocytes) and chronic (lymphocytes and plasma cells) inflammatory cells infiltrate the infected areas of the choroid and retina. Hemorrhage is present in all retinal layers and occasional choroidal hemorrhage occurs. Granulomata contain rare giant cells. Contiguous inflammation of the choroid and retina is present as a rule. Fungal hyphae may be seen spreading on the surface of Bruch’s membrane without penetrating it. Vitreous inflammatory cells are composed mainly of polymorphonuclear leukocytes. Fungal hyphae often are surrounded by macrophages and lymphocytes, which form small vitreous abcesses. Unlike candida endophthalmitis, in which the vitreous is the primary focus of infection, aspergillus endophthalmitis is marked by retinal and choroidal vessel invasion and subretinal pigment epithelial and subretinal infection.
Endogenous aspergillus endophthalmitis must be treated aggressively with diagnostic and therapeutic PPV combined with intravitreal injection of 5–10?µg of amphotericin B. The amphotericin B may be reinjected weekly, but the cumulative intravitreal dose should be kept below 25?µg. Intravitreal corticosteroids may be used in conjunction with amphotericin B to reduce severe postoperative inflammatory response.  Because most patients with endogenous aspergillus endophthalmitis have disseminated aspergillosis, systemic treatment with intravenous amphotericin B is usually required. Other systemic antifungal agents such as itraconazole, miconazole, fluconazole, and ketoconazole may be used also. Systemic aspergillosis is best managed by an infectious disease specialist. The value of systemic antifungal agents in isolated ocular disease is unknown and controversial.
COURSE AND OUTCOME
Despite aggressive treatment, the visual prognosis is dismal. The final visual outcome is poor because of macular involvement. Most eyes have final visual acuity of less than 20/200. Repeated operations to remove cataract, epiretinal membranes, or to control recalcitrant infection are not uncommon.   Close follow-up during the first 3 months after surgery is required.
COCCIDIOIDES IMMITIS—OCULAR COCCIDIOIDOMYCOSIS
Coccidioidal uveitis should be considered for anyone with an apparent idiopathic iritis who has lived or traveled through endemic areas of the American Southwest, specifically southern California and the San Joaquin Valley, northern Mexico, or Argentina.
Intraocular manifestations of coccidioidomycosis consist of iridocyclitis, iris granuloma ( Fig. 171-4, A ), choroiditis, or chorioretinitis. 
Systemic coccidioidal infection usually is present and complement fixation titers are elevated (>1:32). Rarely, the eye may be the only organ involved.   With isolated anterior segment involvement, an anterior chamber sample may be useful. Culturing for the organism may result in delayed diagnosis. The material from the anterior chamber sample may be examined directly for coccidioidal organisms using the Papanicolaou stain.
The differential diagnosis of coccidioidal uveitis is given in Box 171-3 .
Figure 171-4 Anterior chamber coccidioidal granuloma causing pupillary block. A, Note the fungating nature of the lesion. B, Biopsy of the lesion revealed coccidioidal spherules.
Differential Diagnosis of Coccidioidal Uveitis
• Candida endophthalmitis
• Tuberculous uveitis
• Aspergillus endophthalmitis
• Histoplasma endophthalmitis
Histopathologically, C. immitis evokes pyogenic, granulomatous, and mixed reactions. Intraocular lesions from the anterior segment usually demonstrate zonal granulomatous inflammation that involves the uvea and angle structure, and coccidioides organisms usually are seen ( Fig. 171-4, B ).
The treatment of intraocular coccidioidomycosis consists of administration of intravenous amphotericin B. The role of intraocular injections of this agent remains unclear. With systemic disease, much higher doses of intravenous amphotericin B may be needed. The role of systemic itraconazole in the treatment of intraocular coccidioidomycosis is unclear. Involvement of the infectious disease specialist is essential in these cases, because it is often difficult to determine when systemic therapy may be discontinued.  
COURSE AND OUTCOME
Prognosis for patients who have ocular coccidioidomycosis is poor. Most eyes require enucleation due to pain and blindness, despite aggressive treatment.  
OTHER FUNGAL UVEITIS
Endogenous fungal endophthalmitis due to Cryptococcus neoformans, Sporothrix schenckii, and Blastomyces dermatitidis are less common than those due to Candida and Aspergillus. Cryptococcal retinochoroiditis occurs in immunosuppressed patients, particularly those with acquired immunodeficiency syndrome and lymphoma. It often is associated with meningitis. Both S. schenckii and B. dermatitidis tend to cause panuveitis, endophthalmitis and, in the case of Blastomyces, multifocal chorioretinitis.  Sporotrichosis often is found in horticulturists. North American systemic blastomycosis usually is concurrently present in cases of blastomycotic panuveitis. These infections often require intraocular as well as systemic therapy with amphotericin B, itraconazole, or ketoconazole.
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