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Coccidioidomycosis is caused by the endemic dimorphic fungus, Coccidioides spp. Two species, Coccidioides posadasii and C. immitis, have been identified using molecular and biogeographic characteristics. C. immitis appears to be confined mainly to California; C. posadasii is more widely distributed through the southwestern United States, northern Mexico, and Central and South America. Most reported infections in these areas represent new infections. Clinical illnesses caused by each are indistinguishable. Infection results from inhalation of spores produced by the fungal form in arid environments with hot summers preceded by rainy seasons (316DiCaudo DJ. Coccidioidomycosis: a review and update. J Am Acad Dermatol 2006;55:929-42., 317Crum NF, Lederman ER, Stafford CM, et al. Coccidioidomycosis: a descriptive survey of a reemerging disease. Clinical characteristics and current controversies. Medicine (Baltimore) 2004;83:149-75.). Infections in regions in which coccidioidomycosis is not endemic usually result from reactivation of a previous infection. Contaminated fomites, such as dusty clothing or agricultural products, also have been implicated as sources of infection (318Stagliano D, Epstein J, Hickey P. Fomite-transmitted coccidioidomycosis in an immunocompromised child. Pediatr Infect Dis J 2007;26:454-6.).

Preexisting impairment of cellular immunity is a major risk factor for severe primary coccidioidomycosis or relapse of past infection. In HIV-infected adults, both localized pneumonia and disseminated infection usually are observed in persons with CD4 counts <250 cells/mm³ (319Ampel 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., 320Ampel NM. Coccidioidomycosis in persons infected with HIV-1. Ann N Y Acad Sci 2007: 111:336-42.). The threshold for risk in HIV-infected children has not been determined; systemic fungal infection has occurred when CD4 counts were ≤100 cells/mm³ and with CD4 <15%, both indicative of severe immunosuppression (1Dankner WM, Lindsey JC, Levin MJ, et al. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J 2001;20:40-8., 15CDC. Guidelines for preventing opportunistic infections among HIV-infected persons-2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. MMWR 2002;51(No. RR-8).). Although no cases of coccidioidomycosis OI were reported in HIV-infected children from the Perinatal AIDS Collaborative Transmission Study, the study sites are not representative of the areas endemic for coccidioidomycosis (4Nesheim SR, Kapogiannis BG, Soe MM, et al. Trends in opportunistic infections in the pre- and post-highly active antiretroviral therapy eras among HIV-infected children in the Perinatal AIDS Collaborative Transmission Study, 1986-2004. Pediatrics 2007;120:00 100–9.). Data are limited in children, but in adults, HAART appears to be responsible for the declining incidence of coccidioidomycosis (321Ampel NM. Coccidioidomycosis among persons with human immunodeficiency virus infection in the era of highly active antiretroviral therapy (HAART). Semin Respir Infect 2001;16:257-62.).

Immunocompromised persons and previously healthy blacks, Hispanics, and Filipinos with coccidioidomycosis are at increased risk for dissemination, as are pregnant women who acquire coccidioidal infection during the second or third trimester. Clinical manifestations of coccidioidomycosis in HIV-infected adults are well described. Among these are diffuse pulmonary disease; focal pneumonitis in less immunocompromised patients; extrathoracic dissemination to meninges, lymph nodes, or liver; fever and weight loss syndrome with positive serologies; and the asymptomatic person with positive serologic tests (320Ampel NM. Coccidioidomycosis in persons infected with HIV-1. Ann N Y Acad Sci 2007: 111:336-42.). If untreated, a coccidioidal antibody-seropositive, HIV-infected person is at risk for serious disease. Bone and joint involvement is rarely observed in HIV-infected patients (321Ampel NM. Coccidioidomycosis among persons with human immunodeficiency virus infection in the era of highly active antiretroviral therapy (HAART). Semin Respir Infect 2001;16:257-62., 322Ampel NM. Coccidioidomycosis in persons infected with HIV type 1. Clin Infect Dis 2005;41:1174-8.).

Children with primary pulmonary infection may present with fever, malaise, and chest pain. The presence of cough varies, and hemoptysis is rare. Persistent fever may be a sign of dissemination to extrathoracic sites. Children with meningitis may present with headaches, altered sensorium, vomiting, and focal neurologic deficits. Fever is sometimes absent, and meningismus occurs in 50% of patients. Hydrocephalus is common and may occur early. Generalized lymphadenopathy, skin nodules or ulcers, peritonitis, and liver abnormalities also may accompany disseminated disease.

Because signs and symptoms are nonspecific, coccidioidomycosis should be considered strongly in regions where it is endemic. Coccidioidomycosis also has been reported in regions where it is not endemic, and diagnostic evaluations should be considered in those areas as well.

In patients with meningitis, the CSF shows moderate hypoglycorrhachia, elevated protein concentration, and pleocytosis with a predominance of mononuclear cells. CSF eosinophilia has been reported.

The observation of distinctive spherules containing endospores in histopathologic tissue or clinical specimens is diagnostic. However, stains of CSF in patients with meningitis usually are negative. Pyogranulomatous inflammation with endosporulating spherules is seen readily with hematoxylin and eosin. Spherules can be observed using cytologic staining methods, such as Papanicolau and Gomori methenamine silver nitrate stains. However, cytologic stains are less useful for diagnosing pulmonary coccidioidomycosis than for diagnosing Pneumocystis jirovecii, and a negative cytologic stain on a clinical respiratory specimen does not rule out possible active pulmonary coccidioidomycosis (322Ampel NM. Coccidioidomycosis in persons infected with HIV type 1. Clin Infect Dis 2005;41:1174-8.). Potassium hydroxide stains are less sensitive and should not be used (DIII) (322Ampel NM. Coccidioidomycosis in persons infected with HIV type 1. Clin Infect Dis 2005;41:1174-8.).

Growth of Coccidioides spp. is supported by many conventional laboratory media used for fungal isolation at 30ºC-37ºC (86ºF-99ºF) with growth occurring within 5 days (322Ampel NM. Coccidioidomycosis in persons infected with HIV type 1. Clin Infect Dis 2005;41:1174-8.). However, blood cultures are positive in <15% of cases and <50% of CSF from children with meningitis will have a positive culture (322Ampel NM. Coccidioidomycosis in persons infected with HIV type 1. Clin Infect Dis 2005;41:1174-8.). In contrast, cultures of respiratory specimens are frequently positive in cases of pulmonary coccidioidomycosis in adults.

Although serologic assays that detect coccidioidal-specific antibody are valuable noninvasive aides in diagnosis, negative assays cannot be used to exclude the diagnosis in the immunocompromised host. In the latter instance, detection of coccidioidin or cross-reacting antigens are important diagnostic tests, especially in severe manifestations of disease. Assays for coccidioidal antibody in serum or body fluids such as CSF provide valuable diagnostic and prognostic information. Cross-reactivity may occur with other endemic mycoses. The presence of IgM-specific coccidioidal antibody suggests active or recent infection. The complement fixation (CF) assay detects IgG-specific antibody. CF titers become undetectable in several months if the infection resolves. Standardized CF titers >1:16 directly correlate with the presence and severity of extrapulmonary dissemination. Serologic tests may be falsely negative in severely immunosuppressed HIV-infected children. CF antibody is present in the CSF of 95% of patients with coccidioidal meningitis, but serial testing may be needed to demonstrate this. Titers decline during effective therapy.

Not applicable.

In addition to monitoring the patient for clinical improvement, monitoring coccidioidal IgG antibody titers by the complement fixation methodology is useful in assessing response to therapy. Titers should be obtained every 12 weeks (AIII). If therapy is succeeding, titers should decrease progressively, and a rise in titers suggests recurrence of clinical disease. However, if serologic tests initially were negative, titers during effective therapy may increase briefly and then decrease (322Ampel NM. Coccidioidomycosis in persons infected with HIV type 1. Clin Infect Dis 2005;41:1174-8.). This lag in response during the first 1 or 2 months of therapy should not be construed as treatment failure.

Adverse effects of amphotericin B are primarily nephrotoxicity. Infusion-related fevers, chills, nausea, and vomiting also can occur, although they are less frequent in children than in adults. Lipid formulations of amphotericin B have lower rates of nephrotoxicity. Hepatic toxicity, thrombophlebitis, anemia, and rarely neurotoxicity (manifested as confusion or delirium, hearing loss, blurred vision, or seizures) also can occur (see discussion on monitoring and adverse events in Candida infection).

Triazoles can interact with CYP450-dependent hepatic enzymes, and the potential for drug interactions should be evaluated carefully before initiation of therapy (AIII). Fluconazole and itraconazole appear to be safe in combination with antiretroviral therapy. Voriconazole should be avoided in patients receiving HIV PIs or NNRTIs (320Ampel NM. Coccidioidomycosis in persons infected with HIV-1. Ann N Y Acad Sci 2007: 111:336-42.). The most frequent adverse effects of fluconazole are GI, including nausea and vomiting. Skin rash and pruritis might be observed, and rare cases of Stevens-Johnson syndrome have been reported. Asymptomatic increases in transaminases occur in 1%-13% of patients receiving azole drugs. In HIV-infected patients, fluconazole at high doses can cause adrenal insufficiency (327Huang YW, Chang CC, Sun HY, et al. Primary adrenal insufficiency in patients with acquired immunodeficiency syndrome: report of four cases. J Microbiol Immunol Infect 2004;37:250-3.).

Coccidioidomycosis disease in response to IRIS has not been described in children.

Clinical information is limited about new therapeutic agents. Posaconazole was effective in six patients with disease refractory to treatment with azoles and amphotericin B (328Anstead GM, Corcoran G, Lewis J, et al. Refractory coccidioidomycosis treated with posaconazole. Clin Infect Dis 2005;40:1770-6.). Voriconazole was effective in treating coccidioidal meningitis and nonmeningeal disseminated disease in patients who did not respond to fluconazole or were intolerant of amphotericin B (329Proia LA, Tenorio AR. Successful use of voriconazole for treatment of Coccidioides meningitis. Antimicrob Agents Chemother 2004;48:2341., 330Prabhu RM, Bonnell M, Currier BL, et al. Successful treatment of disseminated nonmeningeal coccidioidomycosis with voriconazole. Clin Infect Dis 2004;39:e74-7.). Caspofungin alone successfully treated disseminated coccidioidomycosis in a renal transplant patient intolerant of fluconazole and in persons in whom conventional therapy failed (331Hsue G, Napier JT, Prince RA, et al. Treatment of meningeal coccidioidomycosis with caspofungin. J Antimicrob Chemother 2004; 54:292-4., 332Antony S. Use of the echinocandins (caspofungin) in the treatment of disseminated coccidioidomycosis in a renal transplant recipient. Clin Infect Dis 2004;39:879-80.). Others have used caspofungin in combination with fluconazole (333Park DW, Sohn JW, Cheong HJ, et al. Combination therapy of disseminated coccidioidomycosis with caspofungin and fluconazole. BMC Infect Dis 2006: Feb 15;6:26.).

Adjunctive interferon-gamma was successfully used in a critically ill adult with respiratory failure who did not respond to amphotericin B preparations and fluconazole (334Kuberski TT, Servi RJ, Rubin PJ. Successful treatment of a critically ill patient with disseminated coccidioidomycosis, using adjunctive interferon-gamma. Clin Infect Dis 2004;38:910-2.). However, no controlled clinical studies or data exist for children; thus, it is not recommended for use in HIV-infected children (DIII). Patients with coccidioidal meningitis who do not respond to treatment with the azoles might improve with both systemic amphotericin B and direct instillation of amphotericin B into the intrathecal, ventricular, or intracisternal spaces with or without concomitant azole treatment (CI) (325Galgiani JN, Catanzaro A, Cloud GA, et al. Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group. Ann Intern Med 2000;133:676-86., 326Saitoh A, Homans J, Kovacs A. Fluconazole treatment of coccidioidal meningitis in children: two case reports and a review of the literature. Pediatr Infect Dis J 2000;19:1204-8.). The basilar inflammation characteristic of coccidioidal meningitis commonly results in obstructive hydrocephalus, necessitating placement of a CSF shunt. Development of hydrocephalus in coccidioidal meningitis does not necessarily indicate treatment failure.

Relapse can occur in as many as 33% of patients with disseminated coccidioidomycosis, even in the absence of HIV infection, so lifelong antifungal suppression with either fluconazole or itraconazole is recommended for HIV-infected children who have coccidioidomycosis (AII) (322Ampel NM. Coccidioidomycosis in persons infected with HIV type 1. Clin Infect Dis 2005;41:1174-8., 324Galgiani JN, Ampel NM, Catanzaro A, et al. Practice guideline for the treatment of coccidioidomycosis. Infectious Diseases Society of America. Clin Infect Dis 2000;30:658-61., 335Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005;41:1217-23., 336Carmichael JK. Coccidioidomycosis in HIV-infected persons. Clin Infect Dis 2006;42:1059; author reply 1059-60., 337Mathew G, Smedema M, Wheat LJ, et al. Relapse of coccidioidomycosis despite immune reconstitution after fluconazole secondary prophylaxis in a patient with AIDS. Mycoses 2003;46:42-4.). In coccidioidal meningitis, response rates to the azoles can be excellent, but cures are infrequent, and relapse after cessation of therapy is common, occurring in as many as 80% of patients (338Dewsnup 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.). Thus, indefinite continuation of fluconazole therapy is recommended in patients who have coccidioidal meningitis (AII).

As with other disseminated fungal infections, continued suppressive therapy with fluconazole or itraconazole is recommended after completion of initial therapy. Patients with diffuse pulmonary disease, disseminated disease, or meningitic disease should remain on lifelong prophylaxis-even if immune reconstitution is achieved with HAART (322Ampel NM. Coccidioidomycosis in persons infected with HIV type 1. Clin Infect Dis 2005;41:1174-8.) - because of high risk for relapse (AIII). In HIV-infected adults with focal coccidioidal pneumonia who have clinically responded to antifungal therapy and have sustained CD4 count >250 cells/mm³ on HAART, some experts would discontinue secondary prophylaxis after 12 months of therapy with careful monitoring for recurrence with chest radiographs and coccidioidal serology (CIII). However, only a small number of patients have been evaluated, and the safety of discontinuing secondary prophylaxis after immune reconstitution with HAART among children has not been studied extensively. Therefore, for coccidioidomycosis among HIV-infected children, lifelong suppressive therapy is recommended after an acute episode of the disease, regardless of HAART and immune reconstitution (AIII).