eMedicine Specialties > Ophthalmology > Infectious Disease

Coccidioidomycosis

Cynthia A Self, MD, Assistant Professor, Department of Ophthalmology, Boston University School of Medicine
L Raymond DeBarge, MD, Assistant Professor, Department of Ophthalmology, University of Tennessee College of Medicine at Chattanooga

Updated: Mar 8, 2007

Introduction

Background

Coccidioidomycosis is a disease caused by Coccidioides immitis, a dimorphic fungus that thrives in the lower Sonoran Desert ecozone of the Western hemisphere, including Arizona, New Mexico, west Texas, parts of central America, Argentina, northwest Mexico, and the San Joaquin Valley in California. The warm dry climate and sandy saline soil are ideal for growth of the mycelial phase of the fungus. The mold forms hyphae of 2-4 mm, which consist of chains of arthroconidia that later germinate under moist conditions. During dry seasons, winds spread the highly infectious arthrospores and infection occurs through inhalation of contaminated dust. No documented cases of animal-to-human or human-to-human transmission have occurred.

Pathophysiology

In the pulmonary acinus of the host, the arthroconidia convert to the parasitic phase and form large 20- to 80-mm spherules surrounded by a double-walled capsule. Each spherule contains numerous clear endospores 2-4 mm in diameter. Rupture of a spherule releases the endospores, each of which may form a new spherule.

After inhalation of infectious arthrospores, there is a 10- to 14-day incubation period prior to any clinical manifestations. Coccidioidomycosis is asymptomatic in 60% of patients, while others typically have a limited respiratory illness characterized by fever, cough, and malaise. Bronchopneumonia occurs in approximately one fourth of symptomatic patients. Of every 1000 patients with coccidioidomycosis infection, 2-5 develop disseminated coccidioidomycosis from hematogenous spread of endospores. Disseminated coccidioidomycosis has been found in virtually every organ in the body with the exception of the gastrointestinal tract. The most common site of spread is to the skin.

Because coccidioidomycosis is a fungal disease, the main line of defense is T-cell–mediated immunity. Patients with HIV or other cell-mediated immune deficiencies can develop severe pulmonary and disseminated disease. Pregnant women are also at higher risk for developing disseminated disease. However, primary and disseminated coccidioidomycosis usually occurs in healthy individuals.

Ocular involvement occurs secondary to dissemination and is considered rare. The eyelids and conjunctiva are the most common sites. The skin of the eyelids may contain granulomatous foci of Langerhans giant cells and coccidioidal spherules. Phlyctenular conjunctivitis may be seen and represents a hypersensitivity reaction. True mycotic granulomas of the conjunctiva are less common than hypersensitivity conjunctivitis and usually are seen in the presence of skin lesions.

The uvea is the most common site of intraocular disease. A granulomatous iridocyclitis with iris nodules and posterior synechiae may be seen. However, the typical infection is a multifocal choroiditis with many discrete yellow-white lesions less than a disc diameter in size. Vitritis, vasculitis, serous retinal detachment, and retinal haze may occur in the acute phase. Typical coccidioidal granulomas with spherules are seen in the choroid on histopathology. Lesions also have been noted within the optic nerves. There has been one histopathologically documented report of intraretinal granulomas and organisms that occurred in a previously healthy 12-year-old child.

Frequency

United States

The true incidence of ocular coccidioidomycosis is unknown; however, in one series of 10 patients with disseminated coccidioidomycosis, 4 developed evidence of choroidal infection over a 12-month period of observation.

Disseminated disease has a higher frequency in women during the second half of pregnancy and the postpartum period and in patients who are immunosuppressed.

International

Incidence is unknown.

Mortality/Morbidity

Presenting visual acuity of patients reported in the literature ranges from 20/20 to 20/200. Final visual acuity ranges from 20/20 to no light perception, depending on severity, time to diagnosis, and patient compliance with medical therapy and follow-up care.

Race

Racial differences in the development of ocular manifestations of disseminated coccidioidomycosis are unknown. Ethnic origin is a risk factor for disseminated coccidioidomycosis. The following ethnic groups are listed from the highest to lowest risk: Filipino, African American, Native American, Hispanic, Asian, and white. Filipinos are reportedly 180 times as susceptible as whites to developing disseminated disease.

Sex

A slight male preponderance exists.

Age

Disease may occur in all ages, but infants and elderly persons have the worst clinical outcomes.

Clinical

History

• Past medical history includes the following:
  • Medications
  • Pregnancy
  • Immunosuppression
  • Intravenous drug abuse
  • HIV risk factors
  • A history of travel or living in an endemic area (even remote history)
• Review of systems includes the following:
  • Cough
  • Pleuritic chest pain
  • Fever
  • Chills
  • Night sweats
  • Malaise
  • Myalgia
  • Shortness of breath
  • Skin eruptions
  • Headache
  • Weight loss
  • Joint pain
• Ocular history includes the following:
  • Pain
  • Redness
  • Photophobia
  • Decreased vision
  • Tearing
  • Foreign body sensation
  • Floaters
  • Lid swelling
  • Scotoma

Physical

• Eyelids - Lid granuloma
• Conjunctiva - Phlyctenular or follicular conjunctivitis, conjunctival granuloma
• Sclera - Episcleritis or scleritis
• Cornea - Keratitis, granulomatous mutton-fat keratic precipitates
• Anterior chamber - Cell and flare
• Iris - Nodules
• Lens - Cataract, seclusio pupillae (complete adhesion along the pupillary margin)
• Intraocular pressure - Elevation (secondary glaucoma)
• Vitreous - Vitritis
• Retina - Edema, exudate, hemorrhage, serous retinal detachment
• Choroid - Several groups of findings have been reported, as follows:
  • Diffuse choroiditis (usually seen in preterminal patients)
  • Large (400-1000 µm) juxtapapillary infiltrates involving the choroid with variable involvement of the overlying retina
  • Medium (150-400 µm) spherical opacities at the level of the Bruch membrane and sensory retina
  • Small (100-200 µm) peripheral chorioretinal scars of variable elevation and pigmentation with central hypopigmentation
• Retinal vessels - Vascular sheathing

Causes

The cause of the disease is inhalation of the infectious arthrospores and subsequent dissemination within the body to the eye. A defect in cell-mediated immunity may contribute to the likelihood of dissemination.

Differential Diagnoses

Other Problems to Be Considered

Disseminated Candida
Disseminated cryptococcosis
Disseminated blastomycosis

Workup

Laboratory Studies

• Skin tests for C immitis, tuberculosis, and controls to test for anergy: A positive skin test indicates current or previous infection. However, within endemic areas, 50% of adults have a positive test result. Immunocompromised or severely affected patients frequently have a negative skin test result.
• Complement fixation test for immunoglobulin G (IgG) antibodies to C immitis: This test is probably the most useful. Titers greater than or equal to 1:4 indicate recent or current infection. Additionally, the higher the titer, the worse the outcome.

Imaging Studies

• Chest x-ray to determine pulmonary involvement and to help establish a differential diagnosis
• Fluorescein angiogram
  • Fluorescein angiography (FA) is not recommended in the initial workup because it will not help in the differential or initial management. However, if performed, active lesions show late staining.
  • FA is helpful in evaluating choroidal neovascularization that may develop over time in areas of scars where the Bruch membrane is compromised.

Procedures

• Tissue biopsy with fungal smears and culture can be valuable. Biopsy of skin lesions, if present, carries a lower morbidity than aqueous or vitreous aspiration or chorioretinal biopsy. Therapeutic vitrectomy may be performed in conjunction with biopsy, depending on the severity of the vitreous involvement.

Histologic Findings

Tissue obtained from biopsy shows coccidioidal spherules with granulomatous inflammation.

Treatment

Medical Care

Patients with uveitis often have pulmonary or disseminated disease and typically are hospitalized for intravenous antifungal therapy. Once the patient shows a clinical response to therapy, one may consider changing to an oral antifungal and outpatient management.

Surgical Care

If an aqueous or vitreous tap is performed for diagnostic purposes, injection of an intraocular antifungal agent should be considered. Intracameral amphotericin B also should be considered in cases with vision-threatening uveitis.

Consultations

Since ocular coccidioidomycosis represents disseminated disease, obtaining a thorough systemic evaluation in conjunction with an infectious disease specialist is important, especially if neurologic impairment is suspected.

Medication

Intravenous amphotericin B remains the criterion standard for treatment of coccidioidomycosis. Treatment with amphotericin B is justified with severe infection (eg, extensive or rapidly progressive primary disease, disseminated disease, or risk of disseminated disease).

Recently, the use of newer azoles, particularly ketoconazole, fluconazole, and itraconazole, have been used anecdotally in place of the more toxic amphotericin. No controlled trials of these antifungals have been conducted for primary disease; however, the response rate to azoles is lower than to amphotericin B, and relapse occurs in about one third of patients treated with azoles.

Antifungals

Their mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Amphotericin B (Amphocin, Fungizone)

For fungal infections. Polyene antibiotic produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death. Note that liposomal amphotericin B has the advantage of decreased toxicity over conventional amphotericin B, making administration of larger doses possible.

Dosing

Adult

1-5 mg/kg/d IV in 50-mg increments daily or 3 weekly infusions over 21-24 h
Alternatively: 3-5 mg/kg/d IV of liposomal amphotericin B over approximately 120 min
Intravitreal injection: 5-10 mcg of amphotericin B

Pediatric

Administer as in adults

Interactions

Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; the risk of renal toxicity is increased with cyclosporine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Monitor renal function, serum electrolytes, such as magnesium and potassium, liver function, CBC, and hemoglobin concentrations; resume therapy at the lowest level (eg, 0.25 mg/kg) when therapy is interrupted for more than 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in neutropenic patients receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations of drug; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock

Ketoconazole (Nizoral)

For fungal infections. Fungistatic activity. Imidazole broad-spectrum antifungal agent; inhibits synthesis of ergosterol, causing cellular components to leak, resulting in fungal cell death. Use for mild-to-moderate stable coccidioidomycosis.

Dosing

Adult

200 mg PO qd; increase to 400 mg PO qd, if clinically indicated

Pediatric

<2 years: Not established
>2 years: 3.3-6.6 mg/kg/d PO single dose

Interactions

Isoniazid may decrease bioavailability of ketoconazole; coadministration decreases effects of either rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dosage can be adjusted); may decrease theophylline levels

Contraindications

Documented hypersensitivity; fungal meningitis

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Hepatotoxicity may occur; may reversibly decrease corticosteroid serum levels (adverse effects avoided with dose of 200-400 mg/d); administer antacid, anticholinergics, or H2 blockers at least 2 h after taking ketoconazole

Fluconazole (Diflucan)

For fungal infections. Fungistatic activity. Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes. Use for mild-to-moderate stable coccidioidomycosis.

Dosing

Adult

150 mg PO single dose or 400 mg qd depending on severity of infection

Pediatric

3-6 mg/kg PO qd for 14-28 d or 6-12 mg/kg qd depending on severity of infection

Interactions

Levels may increase with hydrochlorothiazides; fluconazole levels may decrease with long-term coadministration of rifampin; coadministration of fluconazole may decrease phenytoin concentrations; may increase concentrations of theophylline, tolbutamide, glyburide, and glipizide; effects of anticoagulants may increase with fluconazole coadministration; increases in cyclosporine concentrations may occur when administered concurrently

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Adjust dose for renal insufficiency; monitor closely if rashes develop, and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death), with underlying medical conditions, such as AIDS or a malignancy, and while taking multiple concomitant medications; not recommended for mothers who are breastfeeding; convenience and efficacy of single dose regimen for treatment of vaginal yeast infections should be weighed against difficulties resulting from higher incidence of adverse reactions reported with oral fluconazole vs intravaginal agents

Itraconazole (Sporanox)

For fungal infections. Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes. Use not defined for coccidioidomycosis.

Dosing

Adult

200 mg PO qd; not to exceed 400 mg/d; increase in 100-mg increments if no improvement (administer >200 mg/d in divided doses)

Pediatric

Not established; suggested dose of 100 mg/d for systemic fungal infections

Interactions

Antacids may reduce absorption of itraconazole; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (lovastatin or simvastatin); may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce itraconazole levels (phenytoin metabolism may be altered)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in hepatic insufficiencies

Follow-up

Further Inpatient Care

• Patients with uveitis should be seen frequently. Check visual acuity, intraocular pressure, grade anterior chamber and vitreous inflammation, and check activity of choroidal lesions. Follow-up care may be spaced according to clinical improvement.

Further Outpatient Care

• Patients should receive follow-up care at yearly intervals to screen for active lesions. There is a case report in the literature of ocular coccidioidomycosis occurring 22 years after primary infection and 9 years after a unilateral pars planitis that had been treated with cryotherapy.

Complications

• Choroidal neovascularization may occur in areas of scarring. Secondary glaucoma may occur from inflammation and its sequelae.

Prognosis

• The prognosis depends on the degree of choroidal involvement and seems to be related to initial visual acuity and initial systemic severity of disease. Typical choroidal scars have been found in patients with mild respiratory infection and in those with more extensive disease.

Patient Education

• Patients must be made aware that the disease may reactivate years later. Additionally, since choroidal neovascularization can occur in areas of scarring and may lead to blindness, patients must understand the importance of yearly follow-up care.

Miscellaneous

Medicolegal Pitfalls

• Patients should be made aware of the importance of medical follow-up care and of the chance of future reactivation of the disease.

Special Concerns

• Pediatric, geriatric, pregnant, and immunocompromised patients generally have worse outcomes.

References

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3. Blumenkranz MS, Stevens DA. Therapy of endogenous fungal endophthalmitis: miconazole or amphotericin B for coccidioidal and candidal infection. Arch Ophthalmol. Jul 1980;98(7):1216-20. [Medline].

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8. Cutler JE, Binder PS, Paul TO, Beamis JF. Metastatic coccidioidal endophthalmitis. Arch Ophthalmol. Apr 1978;96(4):689-91. [Medline].

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Keywords

valley fever, San Joaquin fever, desert fever, desert rheumatism, coccidioidal granuloma, and Posada-Wernicke disease

Contributor Information and Disclosures

Author

Cynthia A Self, MD, Assistant Professor, Department of Ophthalmology, Boston University School of Medicine
Cynthia A Self, MD is a member of the following medical societies: American Academy of Ophthalmology and American Society of Cataract and Refractive Surgery
Disclosure: Nothing to disclose.

Coauthor(s)

L Raymond DeBarge, MD, Assistant Professor, Department of Ophthalmology, University of Tennessee College of Medicine at Chattanooga
L Raymond DeBarge, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Physicians, American Medical Association, and Association for Research in Vision and Ophthalmology
Disclosure: Nothing to disclose.

Medical Editor

Andrew A Dahl, MD, Director of Ophthalmology Teaching, Mid-Hudson Family Practice Institute; Assistant Professor of Surgery (Ophthalmology), New York College of Medicine
Andrew A Dahl, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Ophthalmology, American College of Surgeons, American Medical Association, American Society of Cataract and Refractive Surgery, and Wilderness Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

R Christopher Walton, MD, Professor, Director of Uveitis and Ocular Inflammatory Diseases Service, Assistant Department of Ophthalmology, Assistant Dean for Graduate Medical Education and Continuing Education, University of Tennessee College of Medicine; Consulting Staff, Regional Medical Center, Memphis Veterans Affairs Medical Center, St Jude Children's Research Hospital
R Christopher Walton, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Healthcare Executives, American Uveitis Society, Association for Research in Vision and Ophthalmology, and Retina Society
Disclosure: Nothing to disclose.

CME Editor

Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri
Disclosure: Nothing to disclose.

Chief Editor

Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Hampton Roy Sr, MD is a member of the following medical societies: American Academy of Ophthalmology, American College of Surgeons, and Pan-American Association of Ophthalmology
Disclosure: Nothing to disclose.

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