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Coccidioidomycosis and HIV
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Introduction
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Epidemiology
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Pathogenesis
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Clinical Presentation
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transparent imageAcute Pulmonary Infection
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transparent imageChronic Pulmonary Infection
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transparent imageChronic Infection of Other Organ Systems
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transparent imageDisseminated Disease in the Immunocompromised Host
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Diagnosis
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Treatment
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Outcome
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Prevention
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References
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Related Resources
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Introduction
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Coccidioidomycosis is a fungal infection endemic to the southwestern United States and certain areas of Mexico and Central and South America. Acute infection with Coccidioides immitis often is asymptomatic; however, approximately 40% of infected persons develop clinical manifestations characterized as a flulike syndrome, a severe pneumonia, or, rarely, disseminated disease and death. The acute disease typically resolves spontaneously, but in some patients it progresses to chronic localized disease of the lungs or other organs such as bone, skin, and meninges. Infection with C immitis can become disseminated widely in patients with immunosuppression secondary to malignant diseases, immunosuppressive drugs, or HIV infection. Patients with AIDS most commonly develop diffuse reticulonodular pulmonary involvement as initial presentation of their disseminated coccidioidomycosis. The definitive diagnosis is based on identification of C immitis by microscopy or culture. High complement fixation titers (>1:64) are associated with extrapulmonic spread and predict a poor outcome.

Treatment of disseminated coccidioidomycosis includes systemic antifungal therapy with amphotericin B or azoles. Amphotericin B remains the drug of choice for life-threatening disease. Fluconazole 400 mg daily or itraconazole 200 mg daily may be used to treat nonmeningeal coccidioidomycosis. High-dose fluconazole continued for life has become the preferred treatment in patients with coccidioidal meningitis, except in those patients who fail to respond to this treatment initially. Because relapses of disseminated disease are frequent, continuous treatment with antifungal drugs is recommended, particularly in patients with an underlying immunodeficiency, such as HIV disease.

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Epidemiology
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C immitis is a dimorphic mold found primarily in arid regions throughout the southwestern United States (California, Arizona, New Mexico, southwestern Texas, and southern parts of Utah and Nevada), northern Mexico, Central America, and parts of South America, including Argentina, Venezuela, Columbia, and Brazil.(1) Mycelia of C immitis grow in soil during the rainy season and develop into thick-walled arthroconidia during the dry season. Wind and mechanical disruption of the soil make these arthroconidia easily airborne, and inhaling them leads to infection.(1)

On the basis of skin testing, it has been determined that approximately one third of residents in endemic areas are infected.(2-4) From 1990 to 1995, the incidence of coccidioidomycosis in Arizona increased by 144%.(5) The Arizona Department of Health Services reported that coccidioidomycosis disproportionately affected persons 65 years of age and older and HIV-infected individuals. In 1993, 10% of HIV-infected patients hospitalized in Arizona had a discharge diagnosis of coccidioidomycosis. Of these individuals, 33% died, compared with 10-15% of HIV-infected individuals hospitalized for other reasons. The increase in incidence of coccidioidomycosis in Arizona was attributed to both an increase of HIV-infected individuals moving into Arizona and a change in the weather pattern.(5) In a subsequent case-control study conducted in southern Arizona in 1995-97, being of black race, not taking antiretroviral therapy, and having a history of oral or esophageal candidiasis were associated significantly with increased risk of developing coccidioidomycosis.(6) Among persons with AIDS in Arizona, the incidence of symptomatic coccidioidomycosis was approximately 4% per year during the study period, representing a significant decrease from previous years and presumably reflecting antiretroviral therapy and increased use of azoles.(6)

The primary infection is asymptomatic in more than 50% of infected persons.(7) Filipino, African American, Native American, or Mexican origin is associated with increased risk of dissemination after primary infection.(8) In patients with documented HIV infection, disseminated coccidioidomycosis is a U.S. Centers for Disease Control and Prevention (CDC) AIDS-defining illness.(9) Coccidioidomycosis is reported in approximately 0.1% of AIDS patients living in nonendemic regions.(10)

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Pathogenesis
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After inhalation, C immitis spores develop a thick wall, forming cystlike spherules in the host tissue; the fungus then multiplies and forms many endospores within the spherules. The spherules eventually burst, giving rise to new spherules and spreading the infection. A granulomatous reaction similar to that in tuberculosis occurs in infected tissue. Local confinement of the infection primarily relies on T-lymphocyte response, although neutrophils and eosinophils also can be found in acute lesions. Humoral factors, particularly complement, also may play some role.(11)

In the immunocompetent host, the acute infection usually is confined to the lung, and resolution is rapid, even though viable fungi may survive in the tissue. In 1-2% of patients (including some who have no apparent immune defect), the disease can take a chronic, waxing and waning course involving the lung or other foci in the musculoskeletal system, skin, lymph nodes, and other organs.(11) Chronic meningitis is a life-threatening complication of dissemination that occurs in a few patients following the acute primary infection.(12,13)

In the patient with immunodeficiency caused by cytotoxic drugs, corticosteroid use, or HIV infection, coccidioidomycosis can present as a fulminant, disseminated infection. Diffuse, progressive involvement of the lungs and other organ systems may occur either during primary infection or as reactivation of a chronic, latent focus.(14,15)

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Clinical Presentation
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Acute Pulmonary Infection
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Only about 40% of patients acutely infected with C immitis experience symptoms. Typically, these patients complain of a flulike syndrome (known as Valley fever or San Joaquin fever in the Central Valley of California) with chest pain and cough.(16) The acute primary infection may present with erythema nodosum or erythema multiforme.(17) Chest radiographs may appear normal or show single or multiple nodules, thin-walled cavities, hilar or mediastinal lymphadenopathy, or pneumonic infiltrates.(18) In the majority of patients, the acute syndrome subsides spontaneously.

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Chronic Pulmonary Infection
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In less than 2% of patients, particularly in those with chronic underlying disease, the primary pulmonary infection evolves into a chronic, waxing and waning process. Pulmonary infection in these patients can lead to cavitation, bronchiectasis, and bronchopleural fistulas with pleural empyema.(18)

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Chronic Infection of Other Organ Systems
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Chronic extrapulmonary foci of C immitis infection may follow early dissemination. The most frequent are abscesses and sinus tract formation of the musculoskeletal system and lytic bone lesions, especially involving the spine.(19,20)

Meningitis is the most life-threatening complication of chronic extrapulmonary coccidioidomycosis.(14) Typically, the onset occurs within a few months of the primary infection and manifests as a chronic meningitis with headache, fever, altered mental status, cranial nerve palsies, and other neurologic deficits. Analysis of the cerebrospinal fluid (CSF) demonstrates a mononuclear pleocytosis, elevated protein levels, and decreased glucose levels. Rarely, a positive finding on CSF antibody test or culture will be the only CSF abnormality indicative of meningitis.(11) Computed tomographic scans of the head may show hydrocephalus.(21) Brain and spinal cord parenchymal involvement with granulomas and abscesses may occur, as may vasculitic complications such as arteritis with focal infarction.(22)

The skin is another common focus of chronic infection, with lesions of highly variable morphology.(23,24) Other sites of chronic infection include the lymph nodes and urogenital system.(7)

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Disseminated Disease in the Immunocompromised Host
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Impairment of T-cell-mediated immune function is associated with significant risk of progressive, disseminated infection with C immitis. Patients with disseminated disease have a relentless clinical course of prominent pulmonary symptoms and multiorgan involvement.(25) The presentation is not specific for the disease. Along with cough, most patients complain of fever, weight loss, and fatigue. Patients may present in septic shock.(26) In a surveillance cohort study in Arizona, 20% required admission to an intensive care unit.(6) Chest radiographs usually show bilateral, diffuse, reticulonodular involvement, but approximately 25% will reveal a focal infiltrate.(6,27) Autopsy reveals small granulomatous lesions in the lungs, lymph nodes, liver, spleen, kidneys, adrenal glands, and other organs.(1,22)

Patients with advanced HIV disease, particularly those with CD4 lymphocyte counts <200 cells/µL, are at increased risk for progressive disseminated C immitis infection.(6,11,28,29) Not all HIV-infected patients with coccidioidomycosis progress to disseminated disease, however, and the clinical manifestations in HIV-infected patients may be similar to those in other populations. In a series of 91 HIV-infected patients with evidence of coccidioidal infection prior to the availability of effective antiretroviral therapy, 65% had diffuse pulmonary disease consistent with disseminated disease, 14% had focal pulmonary disease, 15% had meningitis, and the remaining patients had either isolated involvement of other organs or serologic evidence of the infection without clinical signs.(30) Patients with diffuse disease had lower mean CD4 counts (55 cells/µL) than patients with localized disease (127 cells/µL). The group with diffuse pulmonary disease carried the least favorable prognosis, with a median survival of 54 days. The cumulative mortality in all AIDS patients with coccidioidomycosis was 60%.(30) In the Arizona surveillance study, which included the time frame in which antiretroviral therapy first became available, 88% of patients had CD4 counts <200 cells/µL, and the median CD4 count was 54 cells/µL.(6) Despite receiving antifungal therapy, 25% of patients died within 90 days of the diagnosis of coccidioidomycosis.(6)

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Diagnosis
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The CDC laboratory criteria for diagnosis of coccidioidomycosis are culture-derived, histopathologic, or molecular evidence of C immitis; a positive serologic test for coccidioidal antibodies in serum or CSF by detection of coccidioidal immunoglobulin M (IgM) by immunodiffusion, enzyme immunoassay (EIA), latex agglutination, or tube precipitin, or by detection of rising titer of coccidioidal immunoglobulin G (IgG) by immunodiffusion, EIA, or complement fixation; or a coccidioidal skin test conversion from negative to positive after the onset of clinical signs and symptoms.(5)

Techniques for diagnosis of coccidioidal infection include microscopic detection of the spherules in tissue samples by hematoxylin-eosin staining or silver staining, or isolation of the fungus in culture of tissue or fluids.(31) The fungus will grow from blood or tissue in 3-5 days in various media routinely used for fungal cultures, and addition of cycloheximide may increase the yield.(11,32) Cultures of C immitis must be handled with extreme caution, as the mycelial form contains infectious arthrospores that may become airborne.(31) In pulmonary disease with substantial sputum production, it is possible to detect the fungus in sputum smears or cultures, but detection may require specimens obtained by bronchoalveolar lavage or transbronchial biopsy, the latter having the highest sensitivity.(33) Direct histologic examination or culture also may detect C immitis in tissue samples from bone or skin lesions. CSF cultures are positive in only about 50% of patients with meningitis, including patients with HIV infection, and direct microscopic examination of CSF rarely reveals the organism.(12,21)

Indirect methods for the diagnosis of coccidioidomycosis include skin testing to detect cell-mediated immunity against the fungus and serologic testing for IgM and IgG antibodies in serum or CSF.(11) Skin testing frequently is used in epidemiologic studies to document previous exposure to the fungus. Skin testing may not be useful because the skin test result remains positive long after acute infection has subsided, and is negative for many patients with underlying immunodeficiency and disseminated coccidioidomycosis. Documented conversion in the setting of clinical symptoms, however, fulfills the CDC case definition. The majority of HIV-infected patients have negative skin test results when coccidioidomycosis is diagnosed.(34)

IgM antibody levels rise early in the course of coccidioidomycosis and can be assayed by immunodiffusion or tube precipitation using the mycelial antigen coccidioidin. IgG antibody levels rise after a few weeks of infection but, in contrast to the short-lived IgM response, persist for many months. A complement fixation test usually detects IgG antibodies. More than 90% of patients have IgG antibodies at some point following C immitis infection. Progressive, disseminated disease often is associated with a substantial increase in complement fixation titers (compared with initial titers) and may lead to a transient reappearance of IgM antibodies.(11) Among 88 patients with HIV infection and documented C immitis infection, 60 patients (68%) had evidence of IgM or IgG antibodies on serologic tests, whereas 21 patients (23%) had negative serologic tests, including 17 patients with diffuse pulmonary disease.(30) All CSF samples of 9 patients with advanced HIV disease and coccidioidal meningitis yielded positive results on IgG complement fixation tests.(34) In rare cases, results of CSF complement fixation tests are positive because of a parameningeal focus or because of leakage of antibodies from serum into CSF.(11)

The clinical presentation determines the diagnostic approach to patients suspected of having coccidioidomycosis. In patients with underlying immune deficiency and acute or life-threatening coccidioidomycosis, the goal is to establish the diagnosis early through identification of the fungus from infected tissue; serologic tests for IgM and IgG antibodies should be performed at the time of the initial diagnostic work-up. If the patient is not ill enough to justify invasive procedures, a presumptive diagnosis can be attempted by serologic methods alone. Latex agglutination is a convenient screening test and is highly sensitive, but because of its high false-positive rate, the result must be confirmed by alternative tests for coccidioidal IgM and IgG antibodies.(35,36) There is no evidence to support routine screening of asymptomatic HIV-infected patients from endemic areas for evidence of past coccidioidal infection by skin testing or serology.

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Treatment
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In immunocompetent patients, acute coccidioidomycosis usually is a self-limiting disease requiring no specific treatment. In patients with chronic pulmonary or extrapulmonary C immitis disease, systemic antifungal therapy generally is necessary and may be combined in selected cases with surgical removal of infected tissue (bone, lymph nodes, soft tissue). Local complications of pulmonary disease (hemoptysis, enlarging cavities, pleural empyema, bronchopulmonary fistulas) also may require surgical intervention.(37)

Amphotericin B traditionally had been the treatment of choice, in part due to the lack of randomized controlled trials comparing the various treatment strategies. Most experts favor treating acutely ill patients with disseminated disease with amphotericin B, particularly when the patient is HIV infected or suffers from other immunosuppressive conditions. The recommended regimen is 1 to 1.5 mg/kg/day given intravenously for a cumulative dose of 1 to 2.5 g.(37) Once the acute disease is controlled, lifelong suppressive therapy with ketoconazole (400 mg/day orally) or fluconazole (400-600 mg/day orally) must be instituted in immunosuppressed patients to prevent relapses. Whether initiation of therapy with azoles (fluconazole, itraconazole) in acutely ill HIV-infected patients with disseminated disease is as effective as treatment with amphotericin B currently is not known.(37).

A major role for azoles has been recognized in the treatment of coccidioidal meningitis. In vitro studies have demonstrated activity of many azole compounds (miconazole, ketoconazole, fluconazole, and itraconazole) against C immitis.(38) Mounting clinical evidence indicates that fluconazole, the azole with which there is the most experience, is at least as effective as amphotericin B in the notoriously difficult treatment of this condition, regardless of whether or not patients are HIV infected.(39) Given the practical difficulties of administering amphotericin B intrathecally and the high frequency of associated adverse effects, initiation of fluconazole treatment (800-1,000 mg/day orally) in patients with coccidioidal meningitis has become the preferred initial treatment. Itraconazole also may be effective.(40) Intrathecal amphotericin B should be considered only in patients who do not respond clinically after 1-2 months of therapy.(41) In those cases in which hydrocephalus develops, shunt placement usually is unavoidable.(42) As with other forms of disseminated coccidioidal disease, lifelong therapy is necessary in patients with meningitis.(42,43)

First-line therapy for the treatment of nonmeningeal coccidioidomycosis is fluconazole 400 mg daily or itraconazole 200 mg twice daily.(42,44) A randomized, double-blind, placebo-controlled trial of 198 patients with chronic pulmonary, soft tissue, or skeletal coccidioidal infections compared fluconazole 400 mg daily with itraconazole 200 mg twice daily for 1 year, with a primary endpoint at 8 months.(44) Both HIV-infected and HIV-uninfected participants were enrolled. Forty-seven of 94 patients (50%) randomized to fluconazole, and 61 of 97 patients (63%) randomized to itraconazole, responded to therapy. All 3 of the subgroups classified by primary site of infection showed a trend toward superiority in the itraconazole arm. Although there were more responders in the itraconazole arm at 8 months, there was no significant difference between arms by 12 months. Azole drug levels were not predictive of outcome. Relapse rates after discontinuation of therapy did not differ between the 2 arms (28% for fluconazole, 18% for itraconazole). Of patients with HIV infection, only 5 were randomized to the fluconazole arm and only 2 were randomized to the itraconazole arm; therefore, no inferences regarding the efficacy in HIV-infected patients with coccidioidomycosis can be made.

It is recommended at present that antifungal therapy for HIV-related coccidioidomycosis be continued for life. Whereas studies of HIV-related disseminated histoplasmosis and cryptococcosis have demonstrated that it is safe to discontinue secondary prophylaxis after CD4 counts have improved on antiretroviral therapy, there are no data demonstrating the safety of discontinuing antifungal therapy for coccidioidomycosis in HIV-infected patients with presumed immune reconstitution.

The efficacy of lipid formulations of amphotericin B in the management of coccidioidomycosis is unknown. In a rabbit model of coccidioidal meningitis, liposomal amphotericin B was superior to oral fluconazole and conventional amphotericin B in the clearance of infection.(45) However, there have been no comparative trials in humans. The decision to use any of the lipid formulations should be made on the basis of clinical judgment and expert guidance. Other potential treatment options that warrant further study include caspofungin,(46) posaconazole,(47) and combination therapy such as caspofungin/azole, caspofungin/amphotericin B, and amphotericin B/azole. Although evidence on treatment outcomes in HIV-associated coccidioidomycosis is limited, expert opinion supports offering antifungal therapy to all HIV-infected patients with coccidioidomycosis and favors dual therapy with amphotericin B and an azole in severe disease.(47) In HIV-infected individuals whose focal coccidioidal pneumonia responds quickly to oral therapy and whose CD4 counts were well above 250 cells/µL at the time of coccidioidomycosis diagnosis, it is reasonable to consider either stopping or decreasing the dosage of antifungal medication after 1 year of therapy. Otherwise, for those with disseminated disease, chronic suppression with lifelong antifungal therapy is recommended.(48,49)

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Outcome
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In HIV-infected patients with coccidioidomycosis, the outcome depends largely on the type of infection. Localized infections of the lung seem to be associated with the best prognosis; in one study, only 2 of 20 patients (10%) died during a median follow-up time of 6 months.(33) Disseminated disease, on the other hand, has a dismal prognosis, with a fatality rate of 68% and a median survival of 54 days.(30) The prognosis in patients with meningitis is somewhere between these extremes (33% fatality at 6 months).(34)

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Prevention
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Although HIV-infected people living in or visiting areas endemic for C immitis cannot completely prevent exposure to the arthroconidia, it may be prudent to avoid extensive exposure to dust and soil during the dry season.(50) Whether there is any role for chemoprophylaxis of patients with positive serologies without active disease has not been determined. Unselected chemoprophylaxis in HIV-infected patients living in endemic areas is not recommended, because it is of unproven benefit and may result in the development of resistance to antifungal drugs.

Improved understanding of the epidemiology of this disease can assist in developing more effective prevention strategies. The CDC has recommended the following guidelines (5):

  • Increase the awareness of this disease among clinicians and the public, especially visitors to endemic areas traveling from nonendemic areas.

  • Promote more complete reporting of coccidioidomycosis cases by encouraging all clinical laboratories to report all specimens positive for C immitis.

  • Better characterize the environmental and host factors for acquiring infection.

  • Conduct studies to evaluate the effectiveness of preventing coccidioidomycosis in persons with AIDS or other immunosuppressive conditions who live in endemic regions.

  • Develop an effective vaccine that confers lasting immunity against C immitis.

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References

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47.   Ampel NM. Coccidioidomycosis in persons infected with HIV type 1. Clin Infect Dis 2005; 41:1174-8.
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48.   Mathew G, Smedema M, Wheat LJ, Goldman M. Relapse of coccidioidomycosis despite immune reconstitution after fluconazole secondary prophylaxis in a patient with AIDS. Mycoses 2003; 46:42-4.
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