Coccidioidomycosis is a systemic fungal infection caused by inhalation of spores of Coccidioides immitis and C. posadasii. It is also known as Valley Fever or San Joaquin Valley Fever 1).
The genus Coccidioides inhabits dry soil and desert climates, with endemic areas in the southwestern United States (Arizona, California, western Texas, southern New Mexico), northern Mexico, and Central and South America 1,2). Spores become airborne through soil disturbance from construction, agriculture, or windstorms, leading to inhalation infection.
The incidence is increasing, with 15.2 cases per 100,000 population reported in the United States in 2019 (97% from Arizona and California), approximately three times the 5.3 cases per 100,000 in 1998 1). The actual number of cases is estimated to exceed reported numbers due to low testing rates.
It is a reportable disease to the CDC, with 15,611 cases recorded in 2018. Ocular coccidioidomycosis is rare and occurs secondary to dissemination from a primary infection site such as the lungs, making it difficult to determine the incidence.
Coccidioidomycosis can occur outside endemic areas if there is a history of travel to an endemic area. Additionally, in post-transplant patients who previously lived in an endemic area, there is a risk of reactivation upon initiation of immunosuppressive therapy 1). A detailed history of travel and residence is essential for diagnosis.
Symptoms of ocular coccidioidomycosis vary depending on the affected site.
If systemic symptoms such as fever, malaise, shortness of breath, cough, chest pain, weight loss, headache, migratory joint pain, or night sweats are present, suspect disseminated infection.
The triad of fever, erythema nodosum, and arthralgia, known as “desert rheumatism,” is recognized as typical systemic symptoms1).
Anterior Segment Findings
Phlyctenular and granulomatous conjunctivitis: Caused by a hypersensitivity reaction, often occurring together with erythema nodosum.
Iridocyclitis (granulomatous): Accompanied by “mutton fat” keratic precipitates. Iris nodules may also form in the anterior chamber.
Episcleritis and scleritis: Due to spread of inflammation.
Posterior Segment Findings
Diffuse choroiditis: Extensive choroidal infiltration with retinal sparing.
Chorioretinitis: Juxtapapillary type with hemorrhage, edema, and exudates. Yellow-white opacities on Bruch’s membrane (commonly at the macula and posterior pole).
Endophthalmitis: Most severe finding in disseminated cases. Peripheral chorioretinal scars indicate inactivity.
Extraocular findings include eyelid granuloma, orbital lesions, optic nerve granuloma, atrophy, and cranial nerve palsy (especially abducens nerve palsy). Abducens nerve palsy is known as a finding secondary to increased intracranial pressure in central nervous system coccidioidomycosis.
Coccidioides species form arthroconidia (2–5 microns in length) in soil, which transform into spherules (75–100 microns in diameter) within the alveoli after inhalation1). The spherules produce 100–300 endospores internally, and when they rupture, the released spores form new spherules.
Th2 immunity is considered the primary defense mechanism, as Th2 lymphocyte deficiency or dysfunction is associated with disseminated disease1).
Risk factors for severe disease are listed below.
Diagnosis of coccidioidomycosis is made through a combination of serological tests, fungal culture, and histopathology 1,2).
| Test | Findings | Purpose |
|---|---|---|
| Fluorescein angiography (FA) | Characterization of retinal lesions | Evaluation of chorioretinitis |
| Chest X-ray/CT | Pulmonary lesions/mediastinal lymphadenopathy | Evaluation of primary infection site |
| MRI/CT (orbit/head) | Orbital lesions/CNS dissemination evaluation | Neurological symptoms/orbital lesions |
Definitive diagnosis based solely on ocular findings is difficult; serological tests (IgM and IgG antibodies), travel history to endemic areas, and evaluation of systemic symptoms are important. If biopsy of an extraocular site (skin, lymph nodes, etc.) is possible, it should be performed preferentially. Intraocular biopsy is highly invasive and is reserved for cases where systemic evaluation does not yield a diagnosis.
Treatment decisions are based on the guidelines published by the Infectious Diseases Society of America (IDSA) in 2016.
First-line (mild to moderate):
Severe/refractory cases:
In refractory cases or endophthalmitis, intravitreal administration of voriconazole and amphotericin B has been attempted, but amphotericin B carries a high risk of retinal toxicity. Collaboration with an infectious disease specialist is essential.
Vitrectomy (vitreous surgery) should be considered depending on the extent of vitreoretinal involvement.
Close collaboration with an infectious disease specialist is essential. The infectious disease specialist is responsible for developing and setting the duration of the treatment plan according to IDSA guidelines, which is carried out in parallel with ophthalmologic management. Many cases require long-term suppressive azole therapy.
When inhaled arthroconidia reach the alveoli, they transform into spherules under the influence of body temperature. Spherules grow to 75–100 microns in diameter and contain 100–300 endospores 1). When a spherule ruptures, endospores are released and recognized by the innate immune system (macrophages, neutrophils, dendritic cells), leading to production of inflammatory cytokines such as IL-1, IL-6, IL-12, and TNF-α 1).
As spherules enlarge, innate immune effector cells (neutrophils, monocytes, NK cells) become ineffective, and adaptive immunity (CD4+ T cells → Th1 pathway → IFN-γ production → macrophage activation) takes over. Th2 dysfunction or deficiency is characteristically associated with disseminated disease 1).
If spores remaining after spherule rupture are not eliminated by the immune system, hematogenous dissemination occurs, leading to granulomatous lesions in various organs including the choroidal vasculature. Intraocular lesions typically develop as part of disseminated disease from the lungs.
In the chronic form, granulomas with pulmonary fibrosis and calcification are formed, and in severe cases, dissemination to the meninges (the most direct cause of death), bone marrow, skin, lymph nodes, and eyes occurs1).
Adjuvant therapy with corticosteroids has been attempted for acute respiratory distress syndrome associated with coccidioidomycosis, but its use has traditionally been avoided due to concerns about the risk of enhanced fungal virulence. Its efficacy is still considered limited1).
Genomic analysis of C. immitis and C. posadasii (Neafsey et al., 2010) has revealed interspecies hybridization and gene introgression, advancing the understanding of genetic diversity mechanisms that explain differences in host immune responses1). Elucidating the mechanisms of infection severity and asymptomatic infection remains a future challenge.
Zaheri et al. (2023) reviewed the pathology and treatment options for coccidioidomycosis, highlighting the role of Th2 immunity as a primary defense mechanism and presenting future research topics (elucidation of asymptomatic infection mechanisms, development of more effective prevention strategies)1).
