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Coccidioidomycosis
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Epidemiology

Coccidioidomycosis is caused by a soil-dwelling fungus that consists of two species, Coccidioides immitis and C. posadasii. Most cases in persons with HIV infection have been from the areas in which the disease is endemic, including the Southwestern United States and parts of Central and South America (631Jones JL, Fleming PL, Ciesielski CA, et al. Coccidioidomycosis among persons with AIDS in the United States. J Infect Dis 1995;171:961-6.). However, sporadic cases have been diagnosed outside those areas, presumably as a result of reactivation of a previous infection.

Cellular immunity is critical in controlling coccidioidomycosis. Symptomatic coccidioidomycosis can occur in persons with normal CD4+ concentrations. In patients with no discernible immunodeficiency, disseminated disease occurs in <1%. Black and Filipino men appear to be at higher risk for disseminated disease, as do pregnant women who acquire coccidioidal infection in the second or third trimester.

In patients with HIV infection, immune response to Coccidioides spp. appears to wane with declining CD4+ counts and the risk for developing symptomatic disease in areas in which the disease is endemic increases when this count is <250 cells/µL or with a diagnosis of AIDS (632Ampel NM, Dols CL, Galgiani JN. Coccidioidomycosis during human immunodeficiency virus infection: results of a prospective study in a coccidioidal endemic area. Am J Med 1993;94:235-40.). Retrospective studies have suggested a decline in the incidence of coccidioidomycosis in the areas in which the disease is endemic since the introduction of ART (633Woods CW, McRill C, Plikaytis BD, et al. Coccidioidomycosis in human immunodeficiency virus-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention. J Infect Dis 2000;181:1428-34.).

Clinical Manifestations

Among persons with HIV infection, six common syndromes have been described (634Fish DG, Ampel NM, Galgiani JN, et al. Coccidioidomycosis during human immunodeficiency virus infection: a review of 77 patients. Medicine (Baltimore) 1990;69:384-91.). These are focal pneumonia, diffuse pneumonia (presenting as apparent PCP), cutaneous involvement, meningitis, liver or lymph node involvement, and positive coccidioidal serology tests without evidence of localized infection. Focal pneumonia is most common in those with CD4+ counts >250 cells/µL, whereas the other syndromes usually occur in more immunosuppressed patients. Symptoms of meningitis are headache and progressive lethargy. The CSF profile demonstrates a low glucose with elevated protein and a lymphocytic pleocytosis.

Diagnosis

The diagnosis of coccidioidomycosis is confirmed by culture of the organism from clinical specimens or by demonstration of the typical spherule on histopathologic examination of involved tissue. Blood cultures are positive in a minority of patients, usually in those with diffuse pulmonary disease. Coccidioidal IgM and IgG serology, performed by EIA, immunodiffusion, or classical tube precipitin or complement fixation methodology, is useful in diagnosis although it may be less frequently positive among patients with low CD4+ counts than among immunocompetent persons. Complement fixation IgG antibody is frequently detected in the CSF in coccidioidal meningitis and is useful in establishing this diagnosis. Culture of the CSF is positive in fewer than one third of patients with meningitis.

Preventing Exposure

Although HIV-infected persons cannot completely avoid activities involving extensive exposure to infection while living in or visiting areas in which Coccidioides spp. is endemic, they should avoid activities involving extensive exposure to disturbed native soil, such as occurs at building excavation sites or during dust storms (CIII).

Preventing Disease
Initiating Primary Prophylaxis

Within an area where the disease is endemic, a positive IgM or IgG serologic test indicates an increased risk for the development of active infection (635Arguinchona HL, Arguinchona HL, Ampel NM, et al. Persistent coccidioidal seropositivity without clinical evidence of active coccidioidomycosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1995;20:1281-5.) and specialists would recommend treatment if the CD4+ count is <250 cells/µL (BIII). Yearly testing for seronegative HIV-infected persons living in such regions is reasonable (CIII).

Although highly immunosuppressed patients (633Woods CW, McRill C, Plikaytis BD, et al. Coccidioidomycosis in human immunodeficiency virus-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention. J Infect Dis 2000;181:1428-34.) might benefit from primary prophylaxis, such therapy for HIV-infected persons without a positive IgM or IgG serologic test who live in the area where disease is endemic is not recommended (DIII). However, several clinicians would empirically provide chemoprophylaxis with either oral fluconazole 400 mg daily or itraconazole 200 mg bid if there were a positive IgM or IgG serologic test and the CD4 cell count was <250 cells/µL (CIII). Outside the region in which coccidiodomycosis is endemic, routine testing does not appear to be useful and should not be performed (DIII).

Discontinuing Primary Prophylaxis

If used, primary prophylaxis can be discontinued once peripheral blood CD4+ counts are ≥250 cells/µL for 6 months (CIII). Primary prophylaxis should be restarted if the CD4+ count is <250 cells/µL (BIII).

Treatment of Disease

For patients with clinically mild infection, such as focal pneumonia, or who have a positive coccidioidal serologic test alone, initial therapy with a triazole antifungal is appropriate (BII). Fluconazole or itraconazole at doses of 400 mg daily is recommended (636Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005;41:1217-23., 637Galgiani JN, Ampel NM, Catanzaro A, et al. Practice guideline for the treatment of coccidioidomycosis. Clin Infect Dis 2000;30:658-61.). Data are limited with regard to the newer triazoles, posaconazole and voriconazole, but these agents might be useful in cases that fail to respond to fluconazole or itraconazole. Voriconazole should be used cautiously with HIV PIs and efavirenz.

For patients with either diffuse pulmonary involvement or severely ill patients with extrathoracic disseminated disease, amphotericin B is the preferred initial therapy (AII) (636Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005;41:1217-23.). Most experience has been with the deoxycholate formulation using 0.7-1.0 mg/kg daily as an initial dose. Data regarding lipid formulations of amphotericin B are limited, but these formulations are likely as effective.

Therapy with amphotericin B should continue until clinical improvement is observed. Certain specialists would use a triazole antifungal concurrently with amphotericin B and continue the triazole once amphotericin B is stopped (BIII) (636Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005;41:1217-23.).

Treatment of patients with coccidioidal meningitis requires consultation with a specialist. Therapy should begin with a triazole antifungal. Fluconazole at a dose of 400-800 mg daily is preferred (AII) (638Galgiani JN, Catanzaro A, Cloud GA, et al. Fluconazole therapy for coccidioidal meningitis. Ann Intern Med 1993;119:28-35.), but itraconazole has also been used successfully (639Tucker RM, Denning DW, Dupont B, Stevens DA. Itraconazole therapy for chronic coccidioidal meningitis. Ann Intern Med 1990;112:108-12.). Successful therapy with voriconazole (640Cortez KJ, Walsh TJ, Bennett JE. Successful treatment of coccidioidal meningitis with voriconazole. Clin Infect Dis 2003;36:1619-22.,641Proia LA, Tenorio AR. Successful use of voriconazole for treatment of Coccidioides meningitis. Antimicrob Agents Chemother 2004;48:2341.) and posaconazole (642Anstead GM, Corcoran G, Lewis J, Berg D, Graybill JR. Refractory coccidioidomycosis treated with posaconazole. Clin Infect Dis 2005;40:1770-6.) has been described in case reports. Despite successful antifungal therapy, patients might develop hydrocephalus and require CSF shunting. In some instances, triazole antifungals are not effective. In such cases, intrathecal amphotericin B is recommended (AIII).

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Monitoring the titer of the complement-fixing (CF) antibody is useful in assessing clinical response to therapy. This should be obtained every 12 weeks (AIII). A rise suggests recurrence of clinical disease. IRIS has not been observed in coccidioidomycosis.

Management of Treatment Failure

Patients whose therapy with fluconazole or itraconazole fails might be candidates for newer triazoles, but data regarding both posaconazole and voriconazole are limited. In most such instances, IV amphotericin B, in combination with triazole therapy, is recommended.

Preventing Recurrence

Patients who complete initial therapy for coccidioidomycosis should be considered for lifelong suppressive therapy using either fluconazole 400 mg daily or itraconazole 200 mg twice daily (AII).

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Patients with focal coccidioidal pneumonia who have clinically responded to antifungal therapy appear to be at low risk for recurrence of coccidioidomycosis if their CD4+ counts are >250 cells/µL and they are receiving ART. A reasonable plan for treating such patients is to discontinue secondary prophylaxis after 12 months of therapy (CIII) with continued monitoring for recurrence using serial chest radiographs and coccidioidal serology.

In patients with diffuse pulmonary disease or nonmeningeal disseminated coccidioidomycosis, relapses occur even in patients without HIV infection in 25%-33% of cases (643Catanzaro A, Galgiani JN, Levine BE, et al. Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis. Am J Med 1995;98:249-56., 644Graybill JR, Stevens DA, Galgiani JN, Dismukes WE, Cloud GA. Itraconazole treatment of coccidioidomycosis. Am J Med 1990;89:282-90.). Even in patients with CD4+ counts >250 cells/µL on potent ART, therapy should be continued indefinitely (AIII). For patients with meningitis, relapses have occurred in 80% of patients in whom triazoles have been discontinued (645Dewsnup DH, Galgiani JN, Graybill JR, et al. Is it ever safe to stop azole therapy for Coccidioides immitis meningitis? Ann Intern Med 1996;124:305-10.). On the basis of this evidence, therapy for coccidioidal meningitis should be lifelong (AII).

Special Considerations During Pregnancy

Coccidioidomycosis is more likely to disseminate if acquired during the second or third trimester of pregnancy (646Peterson CM, Schuppert K, Kelly PC, Pappagianis D. Coccidioidomycosis and pregnancy. Obstet Gynecol Surv 1993;48:149-56.). Because of their risk for teratogenicity, azoles should not be used during the first trimester of pregnancy (EII). Neonates born to women on chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia. One problematic area is coccidioidal meningitis, in which the only alternative treatment is intrathecal amphotericin B. For such situations, the decision regarding choice of treatment should be made in consultation with the mother, infectious diseases consultant, and obstetrician.

Prophylaxis to prevent first episode of opportunistic disease: Coccidioidomycosis
IndicationFirst choiceAlternative
Excerpted from Table 1
Definitions of abbreviations: PO = by mouth; bid = 2 times a day
Positive IgM or IgG serologic test in a patient from a disease-endemic area; and CD4+ count <250 cells/µL (CIII)Fluconazole 400 mg PO daily (CIII)

Itraconazole 200 mg PO bid (CIII)

Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Coccidioidomycosis
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Excerpted from Table 2
Definitions of abbreviations: PO = by mouth; tid = 3 times a day; bid = 2 times a day; IV = intrravenous
Preferred therapy for mild infections (focal pneumonia or positive coccidiodal serologic test alone)
transparent gifgrey bulletFluconazole 400 mg PO daily (BII); or
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transparent gifgrey bulletItraconazole 200 mg PO tid x 3 days, then 200 mg bid (BII)
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Certain patients with meningitis may develop hydrocephalus and require CSF shunting

Therapy should be continued indefinitely for patients with diffuse pulmonary or disseminated diseases as relapse can occur in 25%-33% in HIV-negative patients (AIII)

Therapy should be lifelong in patients with meningeal infections as relapse occurred in 80% of HIV-infected patients after discontinuation of triazole therapy (AII)

Case reports of successful therapy with voriconazole and posaconazole are available.
Preferred therapy for severe, nonmeningeal infection (diffuse pulmonary or severely ill patients with extrathoracic disseminated disease): acute phase
transparent gifgrey bulletAmphotericin B deoxycholate 0.7-1.0 mg/kg IV daily (AII)
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transparent gifgrey bulletLipid formulation amphotericin B 4-6 mg/kg IV daily (AIII)
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Duration of therapy: until clinical improvement, then switch to azole

Alternative therapy for severe nonmeningeal infection (diffuse pulmonary or disseminated disease): acute phase
transparent gifgrey bulletCertain specialists add triazole to amphotericin B therapy and continue triazole once amphotericin B is stopped (BIII)
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Preferred therapy for meningeal infections
transparent gifgrey bulletFluconazole 400-800 mg PO or IV daily (AII)
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Alternative therapy for meningeal infections
transparent gifgrey bulletItraconazole 200 mg PO tid x 3 days, then 200 mg PO bid (BII)
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transparent gifgrey bulletIntrathecal amphotericin B when triazole antifungals are not effective (AIII)
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Maintenance therapy (for all cases)
transparent gifgrey bulletFluconazole 400 mg PO daily (AII); or
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transparent gifgrey bulletItraconazole 200 mg PO bid (AII)
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References

631. Jones JL, Fleming PL, Ciesielski CA, et al. Coccidioidomycosis among persons with AIDS in the United States. J Infect Dis 1995;171:961-6.
632. Ampel NM, Dols CL, Galgiani JN. Coccidioidomycosis during human immunodeficiency virus infection: results of a prospective study in a coccidioidal endemic area. Am J Med 1993;94:235-40.
633. Woods CW, McRill C, Plikaytis BD, et al. Coccidioidomycosis in human immunodeficiency virus-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention. J Infect Dis 2000;181:1428-34.
634. Fish DG, Ampel NM, Galgiani JN, et al. Coccidioidomycosis during human immunodeficiency virus infection: a review of 77 patients. Medicine (Baltimore) 1990;69:384-91.
635. Arguinchona HL, Arguinchona HL, Ampel NM, et al. Persistent coccidioidal seropositivity without clinical evidence of active coccidioidomycosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1995;20:1281-5.
636. Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005;41:1217-23.
637. Galgiani JN, Ampel NM, Catanzaro A, et al. Practice guideline for the treatment of coccidioidomycosis. Clin Infect Dis 2000;30:658-61.
638. Galgiani JN, Catanzaro A, Cloud GA, et al. Fluconazole therapy for coccidioidal meningitis. Ann Intern Med 1993;119:28-35.
639. Tucker RM, Denning DW, Dupont B, Stevens DA. Itraconazole therapy for chronic coccidioidal meningitis. Ann Intern Med 1990;112:108-12.
640. Cortez KJ, Walsh TJ, Bennett JE. Successful treatment of coccidioidal meningitis with voriconazole. Clin Infect Dis 2003;36:1619-22.
641. Proia LA, Tenorio AR. Successful use of voriconazole for treatment of Coccidioides meningitis. Antimicrob Agents Chemother 2004;48:2341.
642. Anstead GM, Corcoran G, Lewis J, Berg D, Graybill JR. Refractory coccidioidomycosis treated with posaconazole. Clin Infect Dis 2005;40:1770-6.
643. Catanzaro A, Galgiani JN, Levine BE, et al. Fluconazole in the treatment of chronic pulmonary and nonmeningeal disseminated coccidioidomycosis. Am J Med 1995;98:249-56.
644. Graybill JR, Stevens DA, Galgiani JN, Dismukes WE, Cloud GA. Itraconazole treatment of coccidioidomycosis. Am J Med 1990;89:282-90.
645. Dewsnup DH, Galgiani JN, Graybill JR, et al. Is it ever safe to stop azole therapy for Coccidioides immitis meningitis? Ann Intern Med 1996;124:305-10.
646. Peterson CM, Schuppert K, Kelly PC, Pappagianis D. Coccidioidomycosis and pregnancy. Obstet Gynecol Surv 1993;48:149-56.
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