Coccidioidomycosis (Valley Fever)
Coccidioidomycosis is a systemic fungal disease that rarely presents with ocular manifestations. When present, ocular Coccidioidomycosis can affect any anatomic area of the eye. Due to the potentially devastating outcomes of this disease, there should be a high index of suspicion if a patient presents with systemic and/or pulmonary symptoms in the setting of ocular complaints, especially if the patient is immunocompromised or has recently traveled to areas in which the fungus is endemic. Ocular involvement can potentially be subclinical as well, thus further evaluation should be considered in patients presenting with pulmonary Coccidioidomycosis alone.  Prognosis is guarded, especially with meningeal involvement, however with prompt diagnosis via serology, skin testing, or biopsy, treatment with systemic and potentially intravitreal antifungals can be initiated to ideally prevent the need for enucleation.
Coccidioidomycosis, or San Joaquin Valley Fever, is a systemic fungal disease with a vast array of potential clinical manifestations. The condition results from the inhalation of spores of the Coccidioides species, which include C.immitis and C. posadasii.
Coccidioides species are endemic to southern Arizona, California, southern New Mexico, and west Texas. Coccidioidomycosis infection is reportable to the CDC, and 15,611 cases were recorded in 2018, most of which occurring in these areas where the fungus is endemic. True cases of Coccidioidomycosis may be underreported however, due to low testing rates. Ocular coccidioidomycosis is uncommon and occurs in the setting of dissemination from the primary site of infection, most commonly the lung, making the incidence of this manifestation difficult to determine.
Signs and Symptoms
One-half to two thirds of infections are subclinical, and if patients do experience symptoms, the most common presentation is a self-limited pneumonia. Extrapulmonary manifestations have been well-documented and are more commonly seen in immunocompromised hosts. Coccidioidomycosis has been known to involve the skin, lymph nodes, and bones.
Ocular manifestations have been seen in the anterior segment; intraorbital and extraorbital disease has been reported as well. Anterior segment findings include phlyctenular conjunctivitis, granulomatous conjunctivitis, necrotic conjunctivitis, episcleritis, scleritis, and keratoconjunctivitis. These findings are thought to be secondary to a hypersensitivity response and tend to co-occur with erythema nodosum. Anterior chamber and iris nodules can present as well and can occur concomitantly with anterior uveitis.
Intraocular findings include iridocyclitis, choroiditis, chorioretinitis, and endophthalmitis. The uvea is the most commonly involved intraocular structure, but rarely are both the anterior and posterior tract affected, rather, either the anterior or posterior tract is typically involved. The iridocyclitis seen is granulomatous and is described as having “mutton fat” keratic precipitates. There are several ways in which posterior involvement can present, including diffuse choroiditis sparing the retina; juxtapapillary chorioretinitis with hemorrhage, edema, and exudate; whitish-yellow opacities at Bruch’s membrane with a propensity to involve the macula and posterior pole; and finally, peripheral chorioretinal scarring, more likely indicating inactive disease.
Extraocular findings include lid granulomas and inflammation, lesions of the orbit, optic nerve granulomas and atrophy, and cranial nerve paralysis. Abducens nerve paralysis specifically has been seen as a complication of CNS coccidioidomycosis, likely secondary to increased intracranial pressure. Figure 1 shows an MRI of osteomyelitis from coccidioidomycosis in the superotemporal orbital rim.
Patient-reported symptoms of ocular coccidioidomycosis are dependent on the involved anatomy, but can include redness, foreign body sensation, photophobia, lid inflammation and swelling, tearing, and floaters. Systemic symptoms suggestive of coccidioidomycosis include fever, fatigue, shortness of breath, cough, chest pain, weight loss, headache, migratory arthralgias, maculopapular rash, and night sweats. 
Numerous options are available to diagnose coccidioidomycosis, including serological testing, fungal cultures, and histopathology. Skin testing is once again available in the United States as of 2014. Serological tests can be positive in patients exposed to the fungus without disease, and those with disease may have negative serology, thus somewhat limiting the usefulness of these tests. Early on in infection, these markers can be negative as well. Tissue biopsy provides a definitive diagnosis, which would ideally be performed at extraocular locations, such as the skin if lesions are present. Aqueous and vitreous biopsies can be performed, as well as biopsies of iris nodules and chorioretinal biopsies, however these are generally considered invasive. Additional ophthalmologic testing is unlikely to assist in diagnosis aside from fluorescein angiography, which may help in characterizing retinal lesions.
The differential will vary depending on the ocular manifestation of the disease.
In 2016, the Infectious Disease Society of America (IDSA) released clinical practice guidelines for the treatment of Coccidioidomycosis. Treatment decisions are based on the severity of illness and whether the patient is immunocompromised. In general, options for systemic medical therapy include oral azoles and/or IV amphotericin B. No specific guidelines were given for ocular coccidioidomycosis, however given that the ocular manifestations are often present in the setting of dissemination, IV amphotericin B would likely be indicated followed by maintenance azole therapy once stabilized. Itraconazole is not recommended for intraocular involvement as this agent does not cross the blood-eye barrier. Fluconazole and voriconazole are thus preferred, as these agents have better ocular penetration. Management should be done in consultation with an infectious disease specialist to determine regimens and length of therapy. Intravitreal voriconazole and/or amphotericin B have been used with success as well, however amphotericin B carries a greater risk of retinal toxicity.
Patient outcomes are dependent on the degree of ocular involvement, the involved structures, time to diagnosis, time to therapy initiation, initial visual acuity, and adherence to medical therapy. Patients are likely to receive long-term suppressive azole therapy to prevent relapses. Final visual acuity ranges from 20/20 to no light perception. Anterior segment coccidioidomycosis carries a worse prognosis than posterior segment involvement, with a significant proportion of those with anterior segment involvement requiring enucleation.
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