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Histoplasmosis is caused by inhalation of microconidia produced by the mycelial form of Histoplasma capsulatum, an endemic dimorphic fungus, and cases have been reported from all continents except Antarctica. It is most highly endemic in the Ohio and Mississippi river valleys. Infections in regions in which histoplasmosis is not endemic often result from travel to these regions. Risk factors predisposing to infection are a CD4 count <150 cells/mm³ and exposure to activities that disturb contaminated sites and result in aerosolization of spores. Because yeast forms of the fungus may remain viable within granulomas formed after successful treatment or spontaneous resolution of infection, late relapse can occur if cellular immune function wanes. Infection can occur during pregnancy, and transplacental infection has rarely been reported (379Whitt SP, Koch GA, Fender B, et al. Histoplasmosis in pregnancy: case series and report of transplacental transmission. Arch Intern Med 2004;164:454-8.).

During the pre-HAART era, histoplasmosis was reported in 2%-5% of HIV-infected adults in regions with endemic disease; rates of 25% have been reported in some cities (380Wheat LJ, Chetchotisakd P, Williams B, et al. Factors associated with severe manifestations of histoplasmosis in AIDS. Clin Infect Dis 2000;30:877-81.). In a highly endemic region, histoplasmosis was the AIDS-defining illness in 25% of adults and 8% of children (381Schutze GE, Tucker NC, Jacobs RF. Histoplasmosis and perinatal human immunodeficiency virus. Pediatr Infect Dis J 1992;11:501-2.). Progressive disseminated histoplasmosis (PDH) occurred in 5% of HIV-infected children in another highly endemic region (M. Kleiman, unpublished data, November 28, 2007). The overall incidence of histoplasmosis in children has not been examined systematically but appeared to be low, even during the pre-HAART era (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.).

Few epidemiologic data have been reported on disseminated histoplasmosis in HIV-infected children and adolescents treated with HAART. In several combined PACTG cohorts, the incidence rate of all non-Candida invasive fungal infection was 0.10 infections per 100 child-years (95% CI 0.05-0.20) during the pre-HAART era, and 0.08 infections per 100 childyears (95% CI 0.03-0.17) during the HAART era (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., 3Gona P, Van Dyke RB, Williams PL, et al. Incidence of opportunistic and other infections in HIV-infected children in the HAART era. JAMA 2006;296:292-300.). These data were contributed from centers that underrepresented the geographic regions of maximal histoplasmosis prevalence; so the statistical power to detect decreases in incidence rates associated with HAART may have been limited. However, none of the rates of domestic endemic fungal infections (e.g., histoplasmosis, coccidioidomycosis, and blastomycosis) are likely to exceed these estimates in HIV-infected children and adolescents.

In children without HIV infection, acute pulmonary manifestations are common, but chronic pulmonary infection has not been described. Because of greater airway pliability in children, airway obstruction from mediastinal lymphadenopathy is more common in children (382Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-25.). Although meningitis is common with progressive disseminated infection in infancy, subacute meningitis and parenchymal lesions characteristic of CNS disease in adults are unusual in children (383Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis 2005;40: 844-52.). Isolated pulmonary granulomas resulting from past infections are common incidental findings in chest radiographs of asymptomatic persons residing in histoplasmosis-endemic regions.

The most frequent clinical manifestation of histoplasmosis in HIV-infected children with AIDS is PDH; PDH is fatal if untreated. Prolonged fever and failure to thrive are uniform presenting complaints. Few reports have been published of presenting signs and symptoms in children with PDH complicating AIDS (381Schutze GE, Tucker NC, Jacobs RF. Histoplasmosis and perinatal human immunodeficiency virus. Pediatr Infect Dis J 1992;11:501-2., 384Saidinejad M, Burns MM, Harper MB. Disseminated histoplasmosis in a nonendemic area. Pediatr Infect Dis J 2004;23:781-2., 385Byers M, Feldman S, Edwards J. Disseminated histoplasmosis as the acquired immunodeficiency syndrome-defining illness in an infant. Pediatr Infect Dis J 1992;11:127-8. 110 MMWR September 4, 2009, 386Pillay T, Pillay DG, Bramdev A. Disseminated histoplasmosis in a human immunodeficiency virus-infected African child. Pediatr Infect Dis J 1997;16:417-8.). However, most are similar to those seen in PDH in otherwise normal infants and in infections in patients with other primary or acquired immunodeficiencies. These include splenomegaly, cough, respiratory distress, hepatomegaly, "septic" appearance, generalized lymphadenopathy, interstitial pneumonitis, cytopenia, coagulopathy, oropharyngeal/GI ulcerations, and erythematous nodular/ ulcerative cutaneous lesions (387Odio CM, Navarrete M, Carrillo JM, et al. Disseminated histoplasmosis in infants. Pediatr Infect Dis J 1999;18:1065-8., 388Leggiadro RJ, Barrett FF, Hughes WT. Disseminated histoplasmosis of infancy. Pediatr Infect Dis J 1988;7:799-805., 389Hughes WT. Hematogenous histoplasmosis in the immunocompromised child. J Pediatr 1984;105:569-75.).

Culture and histopathologic, serologic, antigen-detection, and molecular diagnostic techniques have been developed to aid in diagnosing histoplasmosis (390Wheat LJ. Antigen detection, serology, and molecular diagnosis of invasive mycoses in the immunocompromised host. Transpl Infect Dis 2006;8:128-39., 391Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther 2006;6:1207-21.). Understanding their uses and limitations is essential to interpretating results.

Histoplasmin skin tests are not available and were not useful in diagnosing disseminated disease (388Leggiadro RJ, Barrett FF, Hughes WT. Disseminated histoplasmosis of infancy. Pediatr Infect Dis J 1988;7:799-805., 389Hughes WT. Hematogenous histoplasmosis in the immunocompromised child. J Pediatr 1984;105:569-75.). Although isolation of the fungus using culture is diagnostic, it often requires invasive procedures, is insensitive, and may take 10-30 days to grow. Lysis-centrifugation methodology facilitates growth of H. capsulatum, and a DNA probe permits prompt identification of isolates (392Brandt ME, Warnock DW. Histoplasma, Blastomyces, Coccidioides, and other dimorphic fungi causing systemic mycoses. In Manual of clinical microbiology, 9th ed. P. Murray, ed. 2007;9:1857-65.). Histopathologic demonstration of typical yeast forms in tissue specimens, bone marrow, or peripheral blood can be performed rapidly and, when positive, is highly suggestive of active infection. However, results are positive in 12%-43% of adults with PDH (390). PCR and DNA probes have been developed to detect H. capsulatum DNA in tissues (393Bialek R, Feucht A, Aepinus C, et al. Evaluation of two nested PCR assays for detection of Histoplasma capsulatum DNA in human tissue. J Clin Microbiol 2002;40:1644-7.) and body fluids (394Tang YM, Li H, Durkin MM, et al. Urine polymerase chain reaction is not as sensitive as urine antigen for the diagnosis of disseminated histoplasmosis. Diagn Microbiol Infect Dis 2006;54:283-7.) but are neither sufficiently sensitive nor specific (390Wheat LJ. Antigen detection, serology, and molecular diagnosis of invasive mycoses in the immunocompromised host. Transpl Infect Dis 2006;8:128-39., 391Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther 2006;6:1207-21.).

Interpretation of serologic testing using CF and immunodiffusion methods is problematic in immunocompromised hosts with PDH. CF titers of ≥1:32 to the yeast and/or mycelial antigens or detection of H and/or M bands with the immunodiffusion test are considered strongly suggestive of active or recent infection. However, only 41% of HIV-infected adults are seropositive, compared with 82% of adults with PDH and no underlying immunocompromise (395Tobon AM, Agudelo CA, Rosero DS, et al. Disseminated histoplasmosis: a comparative study between patients with acquired immunodeficiency syndrome and non-human immunodeficiency virus-infected individuals. Am J Trop Med Hyg 2005;73:576-82.). Thus, seronegativity cannot be used to exclude active infection, especially PDH. Although a fourfold increase in CF antibody is diagnostic of active infection, 2-4 weeks is needed to determine this. CF antibody titers of CSF may be useful for diagnosing meningitis. In these instances, the assay should begin with undiluted specimens. Concurrent serum titers should be evaluated to exclude false positivity caused by blood contamination of the CSF (383Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis 2005;40: 844-52.).

Development and refinement of an EIA that rapidly identifies and quantifies histoplasmal antigen in body fluids fills most of the gaps left by other diagnostic methods. EIA is especially suited for evaluating patients with large fungal burdens, a feature of infection in immunocompromised hosts. EIA can detect antigen in serum, bronchoalveolar lavage, and CSF. The reported sensitivity of antigen detection is 91%-92% in adults with PDH, and 95% in adults with AIDS (390Wheat LJ. Antigen detection, serology, and molecular diagnosis of invasive mycoses in the immunocompromised host. Transpl Infect Dis 2006;8:128-39., 391Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther 2006;6:1207-21.); sensitivity in children with underlying immunocompromise and in otherwise normal infants is 100% (388; M Kleiman, unpublished data, November 28, 2007) (396Fojtasek MF, Kleiman MB, Connolly-Stringfield P, et al. The Histoplasma capsulatum antigen assay in disseminated histoplasmosis in children. Pediatr Infect Dis J 1994;13:801-5.).

EIA has necessitated changes in recommendations for specimen submission and interpretation. In contrast to earlier, semiquantitative assays, the third generation EIA is standardized by extrapolating antigen concentrations from a calibration curve that is linear to a value of 39 ng/mL. However, urine antigen concentrations in serious infections frequently exceed this value. In these instances, serum specimens should be followed because maximum serum concentrations are lower than those of urine and thus more likely to be in a range in which differences can be accurately measured. After resolution of the antigenemia, urine concentrations can be followed to monitor the effectiveness of treatment and, thereafter, to identify relapse. Antigenuria is identified in 90% of patients whose histoplasmosis relapses (382Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-25.). The histoplasmal antigen assay demonstrates cross-reactions with blastomycosis, paracoccidioidomycosis, and Penicillium marneffei infections (390Wheat LJ. Antigen detection, serology, and molecular diagnosis of invasive mycoses in the immunocompromised host. Transpl Infect Dis 2006;8:128-39., 391Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther 2006;6:1207-21.).

Antigen is detectable in 75%-81% of immunocompetent hosts with acute, primary pulmonary infection. This occurs early in infection, reflecting the primary fungemia that is aborted by an effective cellular immune response. Thus, antigenuria in a patient with HIV who retains normal cellular immunity may not presage development of disseminated infection.

Diagnosis of CNS infection is difficult, particularly if the patient has isolated meningitis without disseminated disease (383). Highest sensitivity is achieved by testing CSF for histoplasmal antigen, antibody, and large-volume culture. In adults, CSF culture is positive in 20%-60% of patients, CSF antigen is positive in 40%-70%, and CSF antibody is positive in 70%-90% (390Wheat LJ. Antigen detection, serology, and molecular diagnosis of invasive mycoses in the immunocompromised host. Transpl Infect Dis 2006;8:128-39., 391Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther 2006;6:1207-21.); Meningitis frequently accompanies PDH of infancy (387Odio CM, Navarrete M, Carrillo JM, et al. Disseminated histoplasmosis in infants. Pediatr Infect Dis J 1999;18:1065-8.).

Although studies have not been done to support the safety of discontinuing primary prophylaxis, the safety of discontinuing suppressive therapy (secondary prophylaxis) for HIVinfected adults with CD4 counts >150 cells/mm³ has been demonstrated; treatment should be resumed if CD4 count falls below this threshold and the patient continues to reside in an area in which the threshold of >10 cases per 100 patient-years is exceeded (382Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-25., 398Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004;38: 1485-9.). Prophylaxis is not recommended for HIV-infected children (DIII).

Acute primary pulmonary histoplasmosis can present with a wide spectrum of symptoms ranging from dyspnea with high fever and diffuse pulmonary infiltrates to only mild respiratory symptoms, variable fever, and a chest radiograph showing mediastinal adenopathy with or without focal pulmonary infiltrate. For severe or moderately severe symptoms, amphotericin B should be administered for 1-2 weeks; amphotericin B deoxycholate is preferred because it is well tolerated in children (AIII) (382Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-25.). After clinical improvement, patients with intact immunity should receive itraconazole, beginning with a loading dose (see above) for the first 3 days, followed by the recommended doses administered twice daily for at least 12 weeks (AIII); adults with CD4 counts of <150 cells/ mm³, and by extrapolation, HIV-infected children with severe immunosuppression (e.g., CD4 <15% or <150 cells/mm³ in children aged ≤6 years), should receive itraconazole for 12 months (AIII). Urine antigen usually is elevated in these situations and should be monitored to gauge clinical response and, after treatment, identify relapse (AIII).

HIV-infected children, particularly those with functional cellular immunity, occasionally will present with fever associated with mild primary pulmonary infection and histoplasma antigen in the urine. Although an effective cellular immune response may limit such illnesses, treatment with itraconazole for 12 weeks while following histoplasmal urine antigen concentrations may be prudent to ensure concentrations decrease (BIII).

Data from HIV-infected adults suggest that HIV-infected children with moderately severe to severe disseminated histoplasmosis should be treated with an IV amphotericin B formulation for ≥2 weeks or until they clinically improve, followed by itraconazole for 12 months (AI). HIV-infected adults with moderately severe to severe PDH have a higher response rate to treatment with liposomal amphotericin B than with the deoxycholate formulation (88% vs 64%) and a lower death rate (2% vs 13%) (AI) (382Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-25.). After a favorable clinical response, amphotericin B should be discontinued and followed by "step-down" therapy with itraconazole for 12 months (AII). A loading dose (see above) of itraconazole should be used for the initial 3 days. If itraconazole is not well tolerated, a 4- to 6-week course of amphotericin B should be used and histoplasma urine antigen levels followed (AIII).

Although therapeutic trials of amphotericin B deoxycholate used to treat PDH in HIV-infected children have not been performed, this formulation is effective for treating severe PDH in infants (387Odio CM, Navarrete M, Carrillo JM, et al. Disseminated histoplasmosis in infants. Pediatr Infect Dis J 1999;18:1065-8., 402Adderson EE. Histoplasmosis in a pediatric oncology center. J Pediatr 2004;144:100-6.), including those with CNS infection (387Odio CM, Navarrete M, Carrillo JM, et al. Disseminated histoplasmosis in infants. Pediatr Infect Dis J 1999;18:1065-8.), and in children with other primary or acquired immunodeficiency states. Amphotericin B deoxycholate is better tolerated by children than by adults, and it is less costly than other formulations. It may be used if cost or availability of lipid formulations precludes their use (AIII).

Mild to moderate PDH in adults without signs of CNS infection responds favorably in 80%-100% of patients treated with itraconazole monotherapy for 12 months (AII) (382Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-25., 399Dismukes WE, Bradsher RW, Cloud GC, et al. Itraconazole therapy for blastomycosis and histoplasmosis. NIAID Mycoses Study Group. Am J Med 1992;93:489-97.). This regimen also is recommended for HIV-infected children with mild to moderate PDH (AII). A loading dose of itraconazole (see above) should be administered at the onset of treatment and serum concentrations monitored.

CNS infection that accompanies PDH is expected to respond to the regimen recommended for moderately severe to severe PDH. Isolated CNS infection is unusual in children. In adults, frequent failure and relapse are common, and aggressive therapy is recommended. Liposomal amphotericin B is preferred for CNS disease in children and adults because it achieves higher concentrations in the brain (AII); penetration into the CSF is poor with all formulations. The deoxycholate formulation is an alternative. Amphotericin should be administered for 4-6 weeks. Thereafter, the child should receive a loading dose of itraconazole and continuation of itraconazole for 12 months and until CSF abnormalities, including histoplasmal antigen, have resolved (AII). Itraconazole levels should be followed and dose adjusted to ensure optimal serum concentrations (AIII).

In asymptomatic HIV-infected children who have intact cellular immunity and have resided in an area with endemic histoplasmosis, the presence of a typical granuloma in a chest radiograph should prompt evaluation of both histoplasmal urine antigen and CF and immunodiffusion antibody. If any of these tests are positive, treatment with itraconazole for 12 weeks is prudent (BIII). If these tests are negative, therapy need not be used, and clinical follow-up is recommended. In either instance, histoplasmal urine antigen testing should be considered if unexplained fever or other systemic symptoms occur.

In manifestations of histoplasmosis in which antigenuria is demonstrated, antigen levels should be monitored during therapy and for a year thereafter to identify relapse (AIII) (403Wheat LJ, Connolly-Stringfield P, Blair R, et al. Effect of successful treatment with amphotericin B on Histoplasma capsulatum variety capsulatum polysaccharide antigen levels in patients with AIDS and histoplasmosis. Am J Med 1992;92:153-60.). After a recommended course of therapy and, in the absence of symptoms, low-level, stable antigenuria may not constitute a basis for prolonging the recommended course of therapy. Serum levels of itraconazole should be monitored in patients receiving treatment (AIII).

Adverse effects of amphotericin B are primarily nephrotoxicity; permanent nephrotoxicity is related to cumulative dose. Infusion-related fevers, chills, nausea, and vomiting can occur, although they are less frequent in children than in adults. Renal dysfunction and electrolyte imbalances are its primary toxicities; these parameters should be monitored during therapy.

Itraconazole, like other azoles, has relatively low rates of toxicity. GI upset is seen occasionally and its principal toxicity is hepatic. The azole drugs inhibit CYP450-dependent hepatic enzymes so that drug interactions, particularly with antiretroviral drugs, should be carefully evaluated before initiation of therapy.IRIS caused by an inflammatory response to histoplasmosis unmasked by HAART-induced improvement in cellular immunity is unusual, and symptoms are often mild (404Nacher M, Sarazin F, El Guedj M, et al. Increased incidence of disseminated histoplasmosis following highly active antiretroviral therapy initiation. J Acquir Immune Defic Syndr 2006;41:468-70.). In the event of IRIS, antiretroviral therapy should be continued along with antifungal therapy (AIII).

Both voriconazole and posaconazole have been used successfully in a small number of refractory cases in adults (382Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-25.). Because little experience has been reported using the newer azoles and data are limited on use of these agents in children, expert consultation is recommended for cases refractory to first-line agents.

Children responding well after completion of initial amphotericin B treatment should be continued on oral itraconazole maintenance therapy for at least 1 year (AII). Longer-term suppressive therapy with itraconazole may be required in HIVinfected children who are severely immunosuppressed (i.e., CD4 <15% or <150 cells/mm³ in children aged ≥6 years) and patients who experience relapse despite receipt of appropriate therapy (AII) (382Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-25., 398Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004;38: 1485-9.). Fluconazole is less effective than itraconazole (CII), and experience is limited in children with voriconazole.

Discontinuation of treatment has not been examined in children. Data from a clinical trial evaluating discontinuation in adults with immune restoration on HAART suggest discontinuation of itraconazole is recommended in adults if itraconazole has been received for ≥1 year, blood cultures are negative, histoplasmal serum antigen is <2 ng/mL, CD4 counts are >150 cells/mm³, and the patient is compliant with HAART (AI) (398Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004;38: 1485-9.). Extrapolating these recommendations to HIV-infected children on HAART with immune restoration (i.e., CD4 >150 cells/mm³ in children aged ≥6 years) seems reasonable (CIII). Treatment should resume if these parameters are not met. Chronic suppressive therapy is recommended for relapse that occurs despite appropriate treatment (BIII).