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. 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. The primary form that affects humans in the Americas is Histoplasma capsulatum var capsulatum. 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 and up to 25% in hyperendemic cities.[,]. 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.
Pathogenesis and Risk Factors
Histoplasmosis occurs in humans when microconidia are inhaled and transformed into yeast in the lungs. Clinical disease can result from either new infection or reactivation of prior infection. The risk and severity of illness depend on the number of conidia inhaled and the cellular immunity of the host. Annual incidence increases dramatically with CD4 count less than 50 cell/mm3 and 90% of cases occur with a CD4 count less than 200 cells/mm3. Histoplasma capsulatum infects macrophages, which facilitates dissemination. 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. Therefore, patients with HIV are more susceptible to histoplasmosis because of decreased cellular immunity and defective macrophage activity.
Histoplasma infection can be asymptomatic or symptomatic, acute or chronic, and focal or disseminated. 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.[,,] In one outbreak in Indianapolis, 95% of patients with AIDS who developed histoplasmosis developed disseminated disease. Patients with disseminated disease typically present with nonspecific symptoms such as fever, fatigue, anorexia, and weight loss, and hepatosplenomegaly.[,] Approximately 50% of cases include respiratory complaints, and chest radiography often shows diffuse or patchy opacities that can mimic Pneumocystis pneumonia. 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%). 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 with disseminated disease 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. 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. Histoplasma is also more likely to affect the adrenal glands than other endemic mycoses, leading to adrenal insufficiency in a number of cases. Several reports have described hemophagocytic syndrome associated with disseminated histoplasmosis in patients with AIDS.[,]
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. Severely 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.[,] The sensitivity of culture for in AIDS patients with disseminated histoplasmosis is approximately 85% (Figure 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).[,] In a subsequent study that used a more modern third-generation quantitative Histoplasma antigen assay in AIDS patients with disseminated histoplasmosis, the sensitivity was 100% with urinary antigen detection and 92% with serum. Results with the Histoplasma antigen assay are available in 1 to 2 days, compared with culture, which typically takes 2 to 4 weeks to turn positive.[,,] 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.
Treatment for Disseminated Histoplasmosis
For HIV-infected patients suffering from disseminated histoplasmosis, treatment is always indicated, since without treatment, progressive disseminated histoplasmosis is usually fatal. In the 2013 guidelines for the prevention and treatment of opportunistic infections, the recommended treatment regimens for disseminated histoplasmosis vary depending on the severity of disease. For HIV-infected patients with moderately-severe to severe disseminated histoplasmosis, the preferred initial therapy consists of liposomal amphotericin B (AmBisome) at least 2 weeks (or until clinically improved), followed by maintenance therapy with itraconazole (Sporanox) for at least 12 months (Figure 3). If the patient is not able to receive liposomal amphotericin B (based on availability, cost, or intolerance), other lipid formulations of amphotericin B, such as amphotericin B lipid complex (Abelcet), can be used. The itraconazole dose may need adjusting based on interactions with antiretroviral medications or in response to intraconazole serum levels. 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. 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 had greater efficacy and less toxicity than amphotericin B deoxycholate (Figure 4). Itraconazole is not recommended as initial therapy for patients with moderately severe 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). In contrast, the 2013 guidelines for the prevention and treatment of opportunistic infections recommends using itraconazole as initial therapy for patients with less severe disseminated histoplasmosis, followed by itraconazole maintenance therapy for a minimum of 1 year (Figure 5). Several oral alternative agents—posaconazole (Noxafil), voriconazole (Vfend), and to a lesser degree fluconazole (Diflucan)—are considered acceptable for patients intolerant to itraconazole.[,,,] Patients with disseminated disease and concomitant Histoplasma meningitis should receive high-dose liposomal amphotericin B (0.5 mg/kg IV daily) for a longer induction treatment (4 to 6 weeks), followed by itraconazole for at least 12 months.[,] 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 with any itraconazole dose change. Checking levels can also help when assessing for adherence or treatment failure. Patients should have a random serum itraconazole level of at least 1.0 mcg/mL, but levels greater than 10 mcg/mL are unnecessary and likely to cause toxicity.[,] 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. 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. 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. 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).
Long-Term Suppressive Therapy
Traditionally, it was thought that lifelong maintenance therapy was required for all AIDS patients with histoplasmosis to prevent relapse. 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 antiretroviral therapy. All had negative laboratory tests for disease and CD4 counts greater than 150 cells/mm3. There were no relapses after 2 years of follow-up. Accordingly, the 2013 opportunistic infections guidelines recommends the following criteria for stopping long-term suppressive therapy: (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 2 ng/mL, and (4) the CD4 count is greater than 150 cells/mm3 for at least 6 months in response to antiretroviral therapy. Patients should restart long-term suppressive therapy if their CD4 count decreases to less than 150 cells/mm3.[,] In addition some patients will require lifelong suppressive therapy with itraconazole 200 mg daily if they do not meet the criteria for stopping long-term suppressive therapy.
Role of Initiating Antiretroviral Therapy
Starting antiretroviral therapy 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 antiretroviral therapy had much better response rates to antifungal therapy (95.5% versus 47.4%) and lower mortality rates. There are documented cases of immune reconstitution inflammatory syndrome (IRIS) in patients with histoplasmosis, but these are uncommon and usually mild in severity. The opportunistic infections guidelines recommend starting antiretroviral therapy as soon as possible after a diagnosis of histoplasmosis and should not be withheld due to a concern of IRIS. Drug-drug interactions are an important consideration when starting antiretroviral in a patient on antifungal therapy, particularly with bidirectional interactions that may occur between the triazole antifungals and certain antiretroviral medication.[,,] In addition, caution and close monitoring is warranted in patients on amphotericin-related compounds and the antiretroviral medication tenofovir, due to combined potential nephrotoxicity.