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Ophthalmic Pearls: Uveitis
Diagnosis and Management of Ocular Coccidioidomycosis
Coccidioidomycosis is a fungal disease that affects about 100,000 Americans a year, with most infections occurring in regions of the Southwest, particularly within the San Joaquin Valley in California. Coccidioidomycosis is primarily a pulmonary infection, with ocular involvement in up to 1 percent of patients who develop disseminated disease. It can affect any adnexal structure and may cause granulomatous conjunctivitis, scleritis, chorioretinitis and endophthalmitis. Individuals who develop disseminated coccidioidomycosis and subsequent ocular involvement are often immunocompromised. However, disseminated coccidioidomycosis may occur in immunocompetent African-Americans, Filipinos and those of Latin American descent.
The incidence of ocular coccidioidomycosis has a slight preponderance in males. Disseminated disease has a higher frequency in women during the second half of pregnancy and the postpartum period compared with the general population. Although the frequency of disease may be higher in pregnant females at a certain stage, the disease course is actually favorable for them compared with the overall group of immunosuppressed patients with disseminated disease.
Coccidioides immitis exhibits a saprophytic and parasitic life cycle. Small arthroconidia, often measuring approximately 6 µm, are inhaled into the host’s pulmonary cavity and transform into thick-walled spherules (30 to 60 µm). The spherules mature and rupture, releasing endospores to spread locally and disseminate hematogenously.
Cellular immunity and neutrophils are both involved in an initial host defense against coccidioidomycosis. Pathologically, coccidioidomycosis is distinguished by a pyogranulomatous reaction, often developing into large abscesses.
It has been estimated that about 40 percent of nonimmune individuals experience symptoms following exposure to C. immitis, while others will experience subclinical infections. A pulmonary illness is most common, with 90 percent of symptomatic patients recovering without treatment and fewer than 1 percent developing a chronic pulmonary form. The most severe cases occur in immunocompromised patients, with two-thirds of these patients exhibiting disseminated disease.
Initial infection. The acute pulmonary form of the disease develops a few weeks after exposure and has a flulike presentation, with associated chest pain, nonproductive cough, fever and malaise. An extensive pulmonary infection may lead to severe dyspnea and respiratory failure. Patients often show patchy infiltrates and mediastinal lymphadenopathy on chest x-ray. Pericardial effusions, joint pain and a nonspecific maculopapular rash are less common manifestations.
Systemic disease. The disseminated form is associated with ocular involvement in up to 1 percent of cases. A septic shock syndrome associated with respiratory failure often precedes this disseminated presentation. The eyelids and conjunctiva are the most common sites for dissemination. Patients with disseminated disease present with systemic symptoms of dyspnea, fever, rash, arthralgias and myalgias before they have ocular symptoms.
Ocular disease. The most common site of intraocular disease is the uvea. Ocular symptoms may include pain, injection, photophobia, decreased or blurry vision, tearing, foreign body sensation, floaters, eyelid swelling and scotomas. The symptoms of multifocal choroiditis may consist particularly of blurred vision, floaters and global orbital pain. Depending on the time of disease presentation and the severity, the visual acuity may range from no light perception to 20/20 in the affected eye.
Ocular Signs and Exam
The intraocular presentation of coccidioidomycosis can include iridocyclitis, iris granulomas, choroiditis and chorioretinitis. Vitritis, vasculitis, serous retinal detachment and retinal haze may occur in acute ocular disease.
Choroidal involvement. Choroidal disease presents with optic disc edema with discrete, scattered choroidal infiltrates that are less than one disc diameter in size. Typical coccidioidal granulomas with spherules are seen in the choroid on histopathology. Patients with choroidal disease also may present with moderate anterior chamber cell, flare and mutton-fat keratic precipitates. The presentation of choroidal infiltrates may be unilateral or bilateral.
Multifocal choroidal disease. Examination findings for multifocal choroiditis include retinal edema, serous retinal detachment, hemorrhage, lipid exudates and yellow-white, fluffy infiltrates. In the choroid, coccidioidomycosis can be further grouped by the size and location of the lesions:
Bilateral retinal dissemination can signal delayed treatment or significant disease progression; diffuse choroiditis usually is seen in preterminal patients.
Diagnosis and Workup
The diagnosis of disseminated coccidioidomycosis usually can be substantiated by positive blood culture. Waiting for cultures may result in a delayed diagnosis and the necessity of starting a nonspecific antifungal regimen. Fungal stains of respiratory secretions or biopsied tissues may show pathognomonic spherules, providing a more rapid diagnosis. Since coccidioidomycosis often starts as a pulmonary disease, bronchoscopy also can improve the yield for diagnosis from the respiratory tract secretions.
Serologic testing. When the disease is associated with focal ocular symptoms, serologic testing with complement fixation titer of 1:32 or greater suggests extensive infection. Often a titer of 1:4 or more is enough to diagnose active infection in most nondisseminated or highly localized infections. With isolated anterior chamber involvement, an anterior chamber sample may be useful. However, waiting for culture growth can lead to a delay in diagnosis.
Other tests. Since most cases of coccidioidomycosis are not isolated to the eye, there are further options for diagnosis, such as skin tests and radiologic imaging. Skin testing often is associated with a false-positive rate of 50 percent in populations where coccidioidomycosis is endemic and in those people with a history of infection.
A chest x-ray or thoracic CT scan can help narrow the differential, but a biopsy with subsequent culturing is needed for definitive diagnosis.
Fluorescein angiography is not typically recommended as part of the workup because it does not assist much in diagnosis or management. However, if angiography is performed as part of additional testing, many of the chorioretinal lesions will exhibit late staining.
Tissue biopsy permits definitive diagnosis of chorioretinitis, with the preferred tissue being from a skin lesion and not an aqueous, vitreal or chorioretinal sample, given the increased risk involved with obtaining such a sample. If the disease process is rather severe, then a diagnostic vitrectomy performed in conjunction with a therapeutic vitrectomy may be of particular benefit. Smears from tissue biopsies will show coccidioidal spherules with zonal granulomatous inflammation.
Various treatment options may be used depending on the extent of intraocular involvement, the presence of underlying immunosuppression and the presence or absence of disseminated disease.
Amphotericin B is the treatment of choice for patients with severe initial disseminated disease involving multiple organs, no tissue diagnosis of C. immitis and with ocular involvement when choroiditis is multifocal. Amphotericin is administered intravenously (0.5 to 1 mg/kg/day) or through intravitreal injection (1.5 µg/0.1 cc). Amphotericin is a fungicidal agent with immunoadjuvant properties. However, one should attempt to avoid amphotericin for prolonged therapy (recurrently for multiple weeks at a time) once cultures or titers have specified C. immitis because of its renal tubular necrotizing effects and poor intraocular penetration.1
Fluconazole 400 to 800 mg/day, orally or intravenously, is the drug of choice for chronic but stable, mildly disseminated disease with subacute, chronic or localized ocular C. immitis infections when ocular presentation is focal. It has significant advantages over amphotericin in being available orally and having high bioavailability, low toxicity and good stability. However, fluconazole does have cross-reactivity with multiple other medications such as rifampin, hydrochlorothiazide, phenytoin, glyburide and theophylline.
The optimal therapy for widely disseminated disease with invasive orbital and chorioretinal involvement is two weeks of intravenous amphotericin with several (two to six) months of IV/ oral fluconazole. Although there have been no trials to date establishing the true efficacy of this combination therapy, the reduced morbidity and mortality rates seen in those clinical cases using this therapy suggest its clinical superiority over monotherapy with fluconazole in patients presenting with chorioretinal disease.2
The few documented cases of focal chorioretinal involvement in patients with disseminated coccidioidomycosis have demonstrated improved vision in all patients with an initial visual acuity of better than 20/100 when using the combination therapy. Maintenance of the improved visual acuity and disease remission may require treatment with fluconazole (200 to 400 mg twice a day) for months or years. However, many eyes will eventually require enucleation because of pain and blindness, despite aggressive combination therapy. Coccidioidomycosis associated with chorioretinal involvement has an associated mortality rate of 30 to 40 percent.
2 Cohen, J. and W. Powderly. Infectious Diseases, 2nd edition (New York: Mosby, 2004), 434–436.
Dr. Ferguson completed his ophthalmology residency through PGY2 and is currently a general medicine physician at Vilseck Health Clinic in Eastern Germany. Dr. Harlan is a vitreoretinal specialist at the Krieger Eye Institute at Sinai Hospital in Baltimore.