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Case 8: Discussion - Disseminated Histoplasmosis

Background and Epidemiology

Histoplasma capsulatum is a dimorphic fungus that grows as a mold at temperatures less than 35°C and as a yeast at temperatures greater than 35°C[1]. Soil enriched with bird or bat guano serves as the main environmental reservoir, so this fungus is often present in or near chicken coops and caves[2]. The primary form that affects humans in the Americas is Histoplasma capsulatum var capsulatum[2]. Histoplasmosis is the most common endemic mycosis affecting AIDS patients living in the United States, with an estimated incidence of 2 to 5% among patients from endemic regions[3]. and up to 25% in hyperendemic cities [4]. Endemic areas include the Ohio and Mississippi river valleys of the United States and many areas of Central and South America; cases have also been reported in Europe, Africa, and Southeast Asia[1].

Pathogenesis and Risk Factors

Histoplasmosis occurs in humans when microconidia are inhaled and transformed into yeast in the lungs[1]. Clinical disease can result from either new infection or reactivation of prior infection[5]. The risk and severity of illness depend on the number of conidia inhaled and the cellular immunity of the host[2]. Annual incidence increases dramatically with CD4 count less than 50 cell/mm3[6], and 90% of cases occur with a CD4 count less than 200 cells/mm3. Histoplasma capsulatum infects macrophages, which facilitates dissemination[1]. Macrophages from HIV-infected patients, especially those with low CD4 cell counts, have decreased ability to recognize and bind the yeast and allow more intracellular growth[7]. Therefore, patients with HIV are more susceptible to histoplasmosis because of decreased cellular immunity and defective macrophage activity[7].

Clinical Manifestations

Histoplasma infection can be asymptomatic or symptomatic, acute or chronic, and focal or disseminated[8]. Immunocompetent individuals usually have mild disease localized to the lungs. In HIV-infected patients, disseminated disease often develops, particularly in those who have a CD4 count less than 150 cells/mm3[3,9]. For example, in one outbreak in Indianapolis, 95% of patients with AIDS who developed histoplasmosis developed disseminated disease[9]. In a prospective study of 304 HIV-infected patients from 1990 to 1993 in Kansas City, 74% of patients with histoplasmosis had symptomatic disease, and 100% of these symptomatic patients had disseminated disease[5]. Untreated disseminated disease usually progresses in an indolent manner over 1 to 3 months, but can be acute and rapidly fatal. Patients typically present with nonspecific symptoms such as fever, fatigue, anorexia, and weight loss[2]. Approximately 50% of cases include respiratory complaints, and chest radiography often shows diffuse or patchy opacities that can mimic Pneumocystis pneumonia, as in the case presented. Less often, the chest radiograph shows focal infiltrates, nodules, or cavities. Patients may also have hepatosplenomegaly (25%), lymphadenopathy (25%), sepsis (10 to 20%), central nervous system involvement (10 to 20%), or gastrointestinal involvement (10 to 20%)[1]. Central nervous system involvement portends a poor prognosis and most commonly manifests as chronic lymphocytic meningitis. Disease can occur anywhere along the gastrointestinal tract and may cause diarrhea, abdominal pain, obstruction, bleeding, or peritonitis. Skin manifestations are present in about 10% of patients and can be papular, maculopapular or pustular in nature, or can occur in the form of ulcerated plaques, erythema multiforme, eczematous rash, or rosacea-like rash[1]. Mucosal lesions occur more often with disseminated histoplasmosis than in most other endemic mycoses and can include superficial ulcerations, deep ulcerations, nodular masses or verrucous lesions of the lips, tongue, gingival pharynx or larynx[2]. Histoplasma is also more likely to affect the adrenal glands than other endemic mycoses, leading to adrenal insufficiency in a number of cases[2]. Common laboratory findings with disseminated histoplasmosis include anemia, leucopenia, thrombocytopenia, elevated alkaline phosphatase, elevated erythrocyte sedimentation rate (ESR), c-reactive protein (CRP) and lactate dehydrogenase (LDH)[2].

Diagnosis

Possible diagnostic methods for histoplasmosis include culture, fungal stains (of body fluids or tissues), serologic testing, and antigen testing. In immunocompetent patients, the sensitivity of serologic tests ranges from 85 to 100%, depending on the type of Histoplasma infection. Immunocompromised HIV-infected patients with histoplasmosis, however, often do not mount a robust antibody response and thus have high false-negative rates with serologic testing. Since these patients usually have disseminated disease with a large fungal load, culture and antigen detection are generally preferred in this setting[10]. The sensitivity of culture for diagnosis of disseminated histoplasmosis in AIDS patients is approximately 85% (Figure 1)[1]. In a study that examined antigen testing of samples from patients with disseminated histoplasmosis during a 5-year period in Indianapolis, antigen testing of urine had the highest yield (95%), followed by serum (86%), cerebrospinal fluid (70%), and bronchoalveolar lavage fluid (70%) (Figure 2). For patients with localized pulmonary disease, antigen testing has poor sensitivity, but for AIDS patients with disseminated disease, it remains the most sensitive test available[3,10]. Antigen detection has a specificity greater than 98%, and results are available in 1 to 2 days, (compared with culture, which typically takes 2 to 4 weeks to turn positive)[1]. Antigen cross-reactivity can occur with coccidioidomycosis, blastomycosis, or paracoccidioidomycosis, but often these can be differentiated by history and epidemiology. In some patients with disseminated disease, blood smears will occasionally show yeasts present within neutrophils[2]. Skin biopsy can provide the fastest diagnosis in patients who have skin disease. In patients with disseminated disease, bone marrow biopsy can be useful and may give a diagnosis more rapidly than antigen testing. Overall, given the significant false-negative rate that occurs with each testing method, most experts recommend sending a combination of tests.

Indications for Treatment

The indications for treatment are summarized in the Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the Infectious Diseases Society of America (IDSA) (Figure 3)[11]. Treatment for histoplasmosis is not generally indicated in mild disease that lasts less than 4 weeks[11]. As described above, however, most HIV-infected patients suffer from disseminated disease, and treatment in these cases is always indicated as it markedly decreases mortality; without treatment, progressive disseminated histoplasmosis is usually fatal[2]. Treatment is also indicated (with good evidence) for moderate to severe acute pulmonary, chronic pulmonary, and central nervous system disease. Though treatment recommendations exist for mild acute pulmonary disease that lasts greater than 4 weeks, severe and persistent mediastinal lymphadenitis, and symptomatic mediastinal granuloma, evidence for these recommendations are described as "moderate" in the 2007 IDSA guidelines and have not been definitively proven[11].

Treatment for Disseminated and Central Nervous System Disease

Treatment regimens for histoplasmosis vary depending on the type and severity of disease. The following treatment recommendations (Figure 4) are based on the 2007 IDSA guidelines for the management of patients with histoplasmosis; these recommendations are not specific to persons with HIV infection[11]. For patients with moderate to severe progressive disseminated infection, the recommended therapy consists of liposomal amphotericin B (AmBisome) for 1 to 2 weeks, followed by itraconazole (Sporanox) for at least 12 months. The itraconazole capsules or solution may be used, but the capsules should be avoided if the patient is taking a histamine-2 receptor blocker or a proton pump inhibitor. Use of amphotericin B lipid complex (Abelcet) may be preferred in some patients because of cost issues or tolerability[11]. In addition, deoxycholate amphotericin B is considered a less expensive possible alternative to lipid formulations of amphotericin and may be considered in patients at low-risk for nephrotoxicity[11].

The preference for liposomal amphotericin B is based on a 2002 study involving AIDS patients with moderately severe to severe disseminated histoplasmosis in which liposomal amphotericin B was associated with greater efficacy and less toxicity than amphotericin B deoxycholate (Figure 5)[13]. Itraconazole is not recommended as initial therapy for patients with moderate to severe disseminated disease based on data that deoxycholate amphotericin B leads to greater clearance of fungal blood cultures than itraconazole (85% versus 53% at 2 weeks), more robust decline in serum antigen levels (1.6 versus 0.1 units at 2 weeks), and larger fall in urine antigen levels (2.1 versus 0.2 units at 2 weeks)[12]. For patients with mild to moderate progressive disseminated histoplasmosis, itraconazole therapy for a minimum of 1 year is recommended [11]. Patients with central nervous system histoplasmosis should receive high-dose liposomal amphotericin B for 4 to 6 weeks[11], followed by itraconazole for at least 12 months.

Treatment for Pulmonary Disease

The first-line recommendation for moderate to severe acute pulmonary histoplasmosis is intravenous liposomal amphotericin B (Ambisome) for 1 to 2 weeks, followed by oral itraconazole for 12 weeks. A 1 to 2 week course of intravenous methylprednisolone is recommended for patients who develop respiratory distress or severe hypoxemia[11]. If disease is mild but persists for longer than 4 weeks, itraconazole is effective (6 to 12 weeks of therapy if disease is localized, or 12 months if disseminated). The recommendations for treatment of patients with histoplasmosis manifesting as chronic cavitary pulmonary disease, broncholithiasis, pulmonary nodules, mediastinal disease, pericarditis, or rheumatologic disease are not discussed here but are provided in detail in the 2007 IDSA guidelines[11].

Alternative Antifungal Agents for Treatment of Histoplasmosis

Fluconazole (Diflucan) has been used to treat histoplasmosis, but studies have shown high rates of relapse and development of resistance, so it is only considered for use when other therapies fail. Ketoconazole (Nizoral) is not generally used because of higher rates of side effects compared with itraconazole[11]. In terms of the newer "azole" drugs, posaconazole (Noxafil) and voriconazole (Vfend) both show in vitro activity against histoplasma; a 2006 study, however, showed that treatment with fluconazole induces cross-resistance to voriconazole[14]. small case series including six patients with severe histoplasmosis who had failed multiple antifungals showed promising results using posaconazole for salvage therapy, but more studies with this drug are needed[15]. Therefore, fluconazole, ketoconazole, posaconazole, and voriconazole are all considered as second-line agents for histoplasmosis[11]. Echinocandins are not recommended for the treatment of histoplasmosis.

Monitoring Patients on Therapy

Because serum levels of itraconazole vary significantly based on absorption, the formulation used (levels are generally higher with the solution than the capsule), and drug interactions, levels should be checked 2 weeks after initiation of therapy or any dose change. Checking levels can also help when assessing for adherence or treatment failure. The exact target level has not been defined, but according to the 2007 IDSA guidelines, it is generally recommended that patients have a random serum itraconazole level of at least 1.0 mcg/mL to prevent treatment failure. Levels greater than 10 mcg/mL are unnecessary and likely to cause toxicity[11]. Because serum itraconazole levels do not vary significantly throughout a 24-hour period, the timing of the blood draw in relation to the last itraconazole dose is not considered important and thus random levels are acceptable[11].

Histoplasma antigen levels can be used to follow the effect of treatment and monitor for relapse. Both serum and urine antigen concentrations decrease throughout the course of therapy, eventually to undetectable levels, although this may take more than a year if the fungal burden is high. If antigen concentrations do not decline with treatment, one should suspect non-adherence, inadequate drug levels, or treatment failure[10]. Antigen levels should be checked before treatment is initiated, at 2 weeks, at 1 month, then every 3 months during therapy. In addition, monitoring of antigen levels should continue for 6 to 12 months after therapy has ended, and any time treatment failure or relapse is suspected. Antigen levels increase in approximately 90% of relapses[11]. In a patient who previously had a decrease in antigen concentration with treatment, a 2-unit or greater increase in serum or urine concentration suggests relapse (a 4-unit or greater increase is more sensitive)[10].

Discontinuing Maintenance Therapy

Traditionally,it was thought that lifelong maintenance therapy was required for all AIDS patients with histoplasmosis to prevent relapse[3]. Available data now suggest that patients with AIDS who have a sustained immunologic response to antiretroviral therapy may safely discontinue histoplasmosis treatment. A prospective study from 2004 followed 32 patients after at least 12 months of antifungal therapy for histoplasmosis and at least 6 months of HAART. All had negative laboratory tests for disease and CD4 counts greater than 150 cells/mm3. There were no relapses after two years of follow-up[16]. Therefore, the 2007 IDSA guidelines state that AIDS patients with disseminated histoplasmosis who are on HAART can safely discontinue itraconazole therapy if the following conditions are met: (1) the patient has completed at least 12 months of itraconazole therapy, (2) fungal blood cultures are negative, (3) serum and urine antigen levels are less than 4 U/mL (less than 2 ng/mL in newer assays), and (4) CD4 count is greater than 150 cells/mm3. Nevertheless, patients require lifelong suppressive therapy with itraconazole 200 mg daily if they suffer a relapse (which occurs in 10-15% of cases), fail HAART, or if their CD4 count decreases to less than 150 cells/mm3[11]. The IDSA guidelines also point out that though the practice of discontinuing therapy is common, the evidence behind it is limited.

Role of Initiating Antiretroviral Therapy

Starting HAART in patients with disseminated histoplasmosis is important because it is associated with better responses to antifungal therapy. In one study, AIDS patients with histoplasmosis who were taking HAART had much better response rates to antifungal therapy (95.5% versus 47.4%) and lower mortality rates[6]. There are documented cases of immune reconstitution inflammatory syndrome (IRIS) in patients with histoplasmosis, but it is rare and usually mild, so HAART should not be delayed for that reason[11]. Drug-drug interactions are an important consideration when starting HAART in a patient on antifungal therapy. In particular, a significant drug-drug interaction may occur between itraconazole and efavirenz (Sustiva, also contained in Atripla). In one case report, this combination lowered plasma itraconazole levels, and the patient developed an increase in urine histoplasma antigen levels. Increasing the dose of itraconazole did not overcome this interaction, and urine histoplasma antigen levels only decreased after the patient switched to a protease-inhibitor based antiretroviral regimen[17]. On the other hand, protease inhibitors, such as lopinavir-ritonavir (Kaletra) or atazanavir (Reyataz) plus ritonavir (Norvir) can have the opposite effect, causing increased levels of itraconazole[17,18].

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    Figure 1 - Estimated Sensitivities of Diagnostic Tests for Disseminated Histoplasmosis in Patients with AIDSFigure 1
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    Figure 2 - Comparison of Histoplasma Antigen Detection Tests in Different Body Fluids in Patients with AIDS and Disseminated HistoplasmosisFigure 2
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    Figure 3 - Indications for Antifungal Treatment for Different Manifestations of Histoplasmosis Figure 3
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    Figure 4 - Recommendations for the Treatment of Severe Manifestations of Histoplasmosis Figure 4
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    Figure 5 - Comparison of Liposomal Amphotericin B and Conventional Amphotericin B for Induction Therapy of Histoplasmosis in Patients with AIDS Figure 5