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Diagnosis and treatment of disseminated histoplasmosis in patients without HIV

Diagnosis and treatment of disseminated histoplasmosis in patients without HIV
Literature review current through: Jan 2024.
This topic last updated: Jan 26, 2024.

INTRODUCTION — Histoplasmosis is a common endemic mycosis that is usually asymptomatic but occasionally results in severe illness. Histoplasmosis and its causative agent, Histoplasma capsulatum, are found worldwide but particularly in North and Central America. Within the United States, infection is most common in the Midwestern states located in the Ohio and Mississippi River valleys. Among the endemic mycoses, it is the most common cause for hospitalization [1]. Histoplasmosis is also a major cause of opportunistic infection in several Latin American countries [2,3].

Disseminated histoplasmosis implies extrapulmonary infection [4]. Silent hematogenous dissemination probably occurs in most persons during the acute infection before cellular immunity develops. Most patients who develop symptomatic disseminated histoplasmosis are immunosuppressed (eg, acquired immunodeficiency syndrome [AIDS], solid organ transplantation, treatment with tumor necrosis factor-alpha inhibitors) or are at the extremes of age. In addition, chronic disseminated histoplasmosis occurs uncommonly in older adults who have no known immunosuppressing conditions. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis", section on 'Risk factors'.)

The diagnosis of disseminated histoplasmosis requires a high index of suspicion, recognition of the common modes of presentation, and familiarity with the appropriate diagnostic tests. Treatment is highly effective, but relapse can occur. The diagnosis and treatment of disseminated histoplasmosis will be reviewed here. The pathogenesis, risk factors for dissemination, and clinical manifestations of this infection and the diagnosis and treatment of pulmonary histoplasmosis are discussed separately. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis" and "Diagnosis and treatment of pulmonary histoplasmosis".)

DIAGNOSIS OF DISSEMINATED HISTOPLASMOSIS

When to suspect the diagnosis — The diagnosis of disseminated histoplasmosis should be suspected in patients with risk factors for disease (eg, immunosuppression or extremes of age and risk factors for exposure) in combination with clinical manifestations that are consistent with disseminated histoplasmosis. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis".)

The most common symptoms of disseminated histoplasmosis are fever, fatigue, and weight loss. Other clinical symptoms depend on the organ system involved. Physical examination, radiographic, and laboratory abnormalities that can be seen in patients with disseminated histoplasmosis include [5]:

Peripheral lymphadenopathy, hepatomegaly, splenomegaly, skin lesions, mucosal lesions, altered mental status, and other neurologic abnormalities.

Anemia, leukopenia, and thrombocytopenia (picture 1).

Elevations in serum aminotransferases, alkaline phosphatase, and/or bilirubin.

Markedly elevated serum lactate dehydrogenase and ferritin values.

Interstitial or reticulonodular infiltrates – Chest radiographs are abnormal in the majority of patients with disseminated histoplasmosis, usually showing diffuse interstitial or reticulonodular infiltrates (image 1); mediastinal adenopathy occurs less often, and cavitation is rare [6-8]. Although diffuse infiltrates are also seen in patients with acute pulmonary histoplasmosis following a large inoculum exposure, in the absence of such an exposure history, diffuse reticulonodular infiltrates suggest disseminated disease, especially in an immunosuppressed patient.

Cerebrospinal fluid findings of lymphocytic pleocytosis, elevated protein, and low glucose concentration.

Single or multiple enhancing brain lesions on computed tomography (CT) scan or magnetic resonance imaging (MRI) (image 2) [9].

Abdominal CT scan showing enlargement of the spleen, adrenal glands, or lymph nodes.

Lesions in the stomach, small intestines, or colon found on gastrointestinal endoscopy.

Establishing the diagnosis — Microscopic demonstration or isolation of Histoplasma from extrapulmonary sites provides proof of dissemination in patients with histoplasmosis. Histopathology using stains for fungi, cultures, antigen detection, tests for Histoplasma-specific antibodies, and PCR can all be used to help make the diagnosis [10-12].

Rapid diagnosis is usually achieved by one of the following methods:

Antigen detection. (See 'Antigen testing' below.)

Cytologic and/or histopathologic examination of tissue samples, respiratory secretions, or body fluids. (See 'Cytology and histopathology' below.)

Wright's stain of blood smears (picture 1).

Serologic tests for antibody to H. capsulatum and culture of the organism are less rapid methods but can aid in confirming the diagnosis of disseminated histoplasmosis. (See 'Antibody tests' below and 'Cultures' below.)

Diagnostic methods

Cultures — Blood cultures should be performed in all suspected cases. Using the lysis-centrifugation technique, cultures are positive in about 65 percent of cases [13-15]. Bone marrow aspiration and biopsy for fungal stains and culture should be performed in patients who are anemic, leukopenic, and/or thrombocytopenic. In patients with diffuse pulmonary infiltrates, H. capsulatum can be cultured from respiratory and lung tissue in the majority of patients [15]. Depending on the sites involved, biopsy of the oral mucosa, skin, gastrointestinal tract, lymph nodes, adrenal glands, or liver can yield the organism in culture [4].

Cytology and histopathology — Biopsy of a skin lesion, mucous membrane lesion, bone marrow, or other tissue can reveal the typical 2 to 4 micron yeast structures that demonstrate a single narrow-based bud of H. capsulatum. Although the organism can sometimes be demonstrated by hematoxylin and eosin stain, H. capsulatum is better visualized using methenamine silver or periodic acid-Schiff (PAS) stains. In one retrospective review, yeasts were seen using fungal stains in respiratory secretions in 86 percent, lung biopsy in 77 percent, and bone marrow in 60 percent of cases [15].

In the unusual circumstance of involvement of vascular structures, as occurs with endocarditis, histopathologic examination may reveal both yeast-like structures and hyphae (picture 2); the presence of hyphae was a prominent finding in a series of 14 cases of Histoplasma endocarditis [16]. Hyphae are not seen in typical cases of disseminated histoplasmosis that involve non-vascular organ systems.

Antibody tests — Both the immunodiffusion test and the complement fixation test should be used in the evaluation of patients with suspected histoplasmosis. Although antibody assays are useful in the diagnosis of the chronic forms of disseminated histoplasmosis, they may be negative in acutely ill patients and are frequently negative in those who are immunocompromised.

In immunocompromised patients, detection of antibody depends upon the population tested. As an example, in one retrospective analysis, antibody was present in 83 percent of patients who had histoplasmosis and who were receiving TNF inhibitors [17]; however, in a series of patients who had undergone solid organ transplant, only 38 percent had antibody present [18]. The low sensitivity for antibody testing in some immunocompromised patients is attributed to the suppressive effects of underlying diseases and/or immunosuppressive medications [19].

An enzyme immunoassay antibody has been used as a screening test by some laboratories, but may be falsely negative in patients who have positive immunodiffusion or complement fixation tests. A newer enzyme immunoassay appears to be more sensitive than immunodiffusion and/or complement fixation in patients with acute pulmonary histoplasmosis [20], but the role of this test in the diagnosis of disseminated histoplasmosis is not clear.

Additional information on serologic testing is found elsewhere. (See "Diagnosis and treatment of pulmonary histoplasmosis", section on 'Serology'.)

Antigen testing — Tests for antigen in urine and serum should be performed in all patients suspected of having disseminated histoplasmosis. Antigen detection in serum may be positive in some cases when the results in urine are negative [19,21,22]. Antigen can also be detected in the cerebrospinal fluid (CSF) in most patients who have central nervous involvement and is a valuable diagnostic test when performed on bronchoalveolar lavage (BAL) fluid in patients who have pulmonary involvement.

Antigen testing is performed using an enzyme immunoassay (EIA). In results from the laboratory that developed this test (MiraVista Diagnostics), Histoplasma antigen was detected in the urine of approximately 75 percent of nonimmunocompromised and 95 percent of immunocompromised patients with disseminated disease [19]. Histoplasma antigen testing is now available from several different commercial laboratories, as well as through reference laboratories [23-28]. Comparison of these assays has shown variable results, but overall, it appears that the commercially available EIA tests are less sensitive than the original EIA [10,26,28]. Thus, a negative assay for antigen in serum or urine does not preclude the diagnosis of disseminated histoplasmosis, since the sensitivity of the various commercially available assays is variable.

False-positive EIA antigen results often occur in patients with blastomycosis and less frequently in patients with coccidioidomycosis, paracoccidioidomycosis, and talaromycosis (caused by Talaromyces marneffei, previously called Penicillium marneffei) [22,29]. False-positive results also have been noted in BAL fluid in patients with aspergillosis [30].

Polymerase chain reaction — The role of polymerase chain reaction (PCR) for diagnosis of histoplasmosis is not established and relies on assays developed and available at individual reference laboratories. One study that evaluated a small number of tissue and respiratory samples found 11 of 15 (73 percent) of culture-positive samples were positive by PCR [31], and in another, PCR was positive only if organisms were seen by microscopy [32]. A nested, real-time PCR assay was noted to have a sensitivity of 77 percent in a small number of clinical samples (serum, tissue, BAL) [33]. Using a real-time quantitative PCR assay that detects whole nucleic acids (both ribonucleic acid [RNA] and deoxyribonucleic acid [DNA]), the French Mycoses Study Group has reported sensitivity as high as 98 percent in patients with proven disseminated histoplasmosis. This assay was especially useful using specimens, including blood samples, taken from immunocompromised patients [34].  

Special considerations for diagnosing meningitis — Establishing the diagnosis of meningitis due to histoplasmosis is difficult. For patients with suspected meningitis, CSF, serum, and urine testing should be obtained as summarized in the table (table 1). (See 'Antigen testing' above and 'Antibody tests' above.)

Among patients with isolated meningitis, the diagnosis is often based upon detection of antigen or antibody in the CSF [9,35-37]. In a report that retrospectively evaluated CSF specimens in patients with a diagnosis of suspected or confirmed central nervous system (CNS) histoplasmosis, the diagnosis was improved when assays for both antigen and IgG/IgM antibody were performed [37]. In this specific study, a newly developed EIA assay for Histoplasma IgG/IgM appeared to perform better than the conventional complement fixation and immunodiffusion assays for detecting antibodies to H. capsulatum in the CSF. (See 'Antibody tests' above.)

Patients with meningitis may also have positive cultures from blood or other tissues. Fungal stains of CSF are rarely positive, and in one large series of 77 cases of Histoplasma CNS infection, only 38 percent of patients had H. capsulatum cultured from CSF [36]. To achieve the best diagnostic yield via culture of CSF, large volumes of CSF (10 to 20 mL) are required on at least two occasions. However, the diagnosis of histoplasmosis cannot be excluded even if large-volume lumbar spinal taps do not yield H. capsulatum.

In rare cases, when all of the above tests are negative, meningeal or brain biopsy may be needed to establish a diagnosis of meningeal or cerebral histoplasmosis [35].

There has been increasing interest in the use of 1,3-beta-D-glucan testing (Fungitell; Associates of Cape Cod, East Falmouth, Massachusetts, United States) in CSF for diagnosing fungal meningitis [38]. 1,3-beta-D-glucan is a cell wall component of many fungi, and during the nationwide outbreak of fungal CNS infections following injection of contaminated methylprednisolone, the beta-D-glucan assay was positive in some patients who had CNS infection with brown-black fungi [39,40]. Subsequent reports noted the utility of this assay in CSF in other fungal infections [41,42]. However, a positive 1,3-beta-D-glucan test alone is neither sensitive nor specific enough to establish the diagnosis of meningitis due to a specific causative organism. In one study of patients with Histoplasma meningitis, the sensitivity and specificity of the 1,3-beta-D-glucan test were 53 and 46 percent, respectively [43]. A positive test in the CSF is most useful in raising suspicion that an unexplained meningitis could be due to a fungus and prompting further testing, such as measuring CSF Histoplasma antigen and Histoplasma antibodies by complement fixation, immunodiffusion, and EIA methodologies [37]. (See 'Antibody tests' above.)

Further diagnostic evaluation — In patients without known underlying risk factors for disseminated histoplasmosis, careful immunologic investigation of cellular immunity, including T cell subset quantitation, should be considered, especially if disease relapses. Tests of lymphocyte proliferative response to H. capsulatum antigens and interferon-gamma release in response to H. capsulatum antigens are being developed and might possibly prove useful for diagnosis in the future [44]. Identification of new defects, such as those described in patients with abnormalities in cytokine pathways, will require specialized testing in laboratories that investigate cellular immune mechanisms [45].

DIFFERENTIAL DIAGNOSIS — The most common symptoms of disseminated histoplasmosis are fever, fatigue, and weight loss. Symptoms and signs may point to involvement of specific sites, such as the oropharynx, gastrointestinal tract, central nervous system, and adrenal glands. (See "Pathogenesis and clinical manifestations of disseminated histoplasmosis".)

The differential diagnosis includes malignancy, infection (eg, tuberculosis, other fungal diseases), or inflammatory disease (eg, inflammatory bowel disease, sarcoidosis). Misdiagnosis of an inflammatory process in a patient who actually has disseminated histoplasmosis may lead to inappropriate and harmful therapy with glucocorticoids, cytotoxic agents, or tumor necrosis factor-alpha inhibitors [46]. (See "Diagnosis and treatment of pulmonary histoplasmosis", section on 'Distinction from sarcoidosis'.)

TREATMENT — The approach to treatment depends upon the severity of disease as well as the presence of central nervous system (CNS) involvement. Our approach to the management of patients with histoplasmosis is consistent with clinical practice guidelines by the Infectious Diseases Society of America [47].

Indications — Treatment is indicated for all patients with disseminated histoplasmosis [47]. The natural history of untreated acute disseminated infection is progressive and fatal over a 2- to 12-week course. The less common chronic form of disseminated histoplasmosis is often present for months before diagnosis [4]. In this chronic form, recurrent illness, separated by asymptomatic periods ranging from several years up to two decades, rarely may be seen, but the disease ultimately will prove fatal if not treated [4].

Patients without CNS disease

Approach to treatment — For patients without central nervous system (CNS) involvement, the treatment of disseminated histoplasmosis typically involves the use of amphotericin B (preferably one of its lipid formulations) or an azole drug, such as itraconazole [48]. Dosing recommendations are discussed below. (See 'Antifungal agents' below.)

Agent selection depends primarily upon disease severity (table 2). Summarized briefly:

Patients with severe disease – One of the lipid formulations of amphotericin B should be used in patients who are sufficiently ill to require hospitalization. Itraconazole is not used for initial therapy in such patients because it does not eradicate fungemia as rapidly as amphotericin B, and serum levels do not reach a steady state for several weeks [49].

Most patients respond quickly to amphotericin B and then can be transitioned to itraconazole after one to two weeks. The transition from amphotericin B to itraconazole should occur after the patient becomes afebrile; no longer requires blood pressure or ventilatory support, or intravenous fluids; and is able to take oral medications. It is helpful to start therapy with itraconazole during the last few days of amphotericin B therapy to make it more likely that serum concentrations of itraconazole will be measurable before amphotericin B therapy is discontinued.

Patients with mild to moderate symptomsItraconazole is the treatment of choice for patients who have mild to moderate symptoms [50,51].

In pregnant women, the approach to treatment must be determined on a case-by-case basis. Azoles are contraindicated in the first trimester because of the risk of teratogenicity, and use later in pregnancy must balance possible risks with benefits.

The total duration of treatment should be at least one year. Although the optimal duration of itraconazole therapy has not been specifically studied, therapy for at least one year is preferred because it may reduce the risk for relapse. However, there are no clinical trials that have studied this. Duration may sometimes need to be extended in patients at high risk for relapse of histoplasmosis because their immunosuppression cannot be reversed (eg, transplant recipients). This is discussed below. (See 'Concurrent immunosuppressive therapy' below.)

If itraconazole is not tolerated, oral therapy with posaconazole, voriconazole, isavuconazole, or fluconazole are other options. However, there are limited data to guide agent selection in this setting. Fluconazole appears to be less effective than itraconazole, and there are data that suggest that voriconazole is not as efficacious as itraconazole [52,53]. The extended-release formulation of posaconazole has advantages over voriconazole because it results in more consistent serum levels and has fewer side effects. There is limited experience with isavuconazole for treatment of histoplasmosis [54]. There are no clinical trials that have directly compared different azoles for treatment of histoplasmosis. When any azole is used, it is important to assess for drug-drug interactions (especially in transplant recipients) and to measure serum concentrations to ensure therapeutic levels and avoid toxicity [55]. (See 'Antifungal agents' below.)

For patients who develop adrenal insufficiency associated with disseminated histoplasmosis, the changes are usually irreversible, and lifelong maintenance hydrocortisone therapy will be required. Patients must be warned about the dangers inherent in stopping replacement therapy. (See "Treatment of adrenal insufficiency in adults".)

Antifungal agents — Information regarding the use of specific antifungal agents for the treatment of disseminated histoplasmosis will be reviewed in this section. Regimen selection is discussed above. (See 'Approach to treatment' above.)

Amphotericin B – The lipid formulations of amphotericin B (eg, AmBisome or Abelcet) require doses of 3 to 5 mg/kg per day (table 2) [56]. If the deoxycholate formulation is used, a dose of 0.7 to 1.0 mg/kg per day is recommended. (See "Pharmacology of amphotericin B".)

A randomized, controlled trial showed that induction therapy with liposomal amphotericin B at a dose of 3 mg/kg/day produced better outcomes than the deoxycholate formulation [56]. Among 81 patients with AIDS and moderately severe to severe disseminated histoplasmosis, liposomal amphotericin B was associated with the following significant benefits: a higher rate of clinical success (88 versus 64 percent) despite similar rates of culture conversion, and lower rates of mortality (2 versus 13 percent), infusion-related side effects (25 versus 63 percent), and nephrotoxicity (9 versus 37 percent).

ItraconazoleItraconazole capsules should be administered with food at a loading dose of 200 mg three times daily for three days to achieve steady-state serum concentrations more rapidly, and then 200 mg twice daily. Acid-blocking drugs should be avoided when the capsule formulation is given. A cola beverage, in addition to a meal, can be administered with the tablets, presumably to increase gastric acidity. (See "Pharmacology of azoles".)

The liquid formulation of itraconazole overcomes problems caused by poor absorption of the capsule formulation and achieves approximately 30 percent higher concentrations in the serum at the same dose. The solution should be given on an empty stomach to achieve the highest serum concentrations. However, more gastrointestinal upset occurs with the solution formulation, which precludes its use in some patients.

A newer formulation of itraconazole with enhanced bioavailability, SUBA-itraconazole, was approved for use in the United States in 2018 [57]. Studies on its use for prophylaxis against invasive fungal infections in recipients of lung transplants and hematopoietic cell transplants have shown efficacy and safety in these populations [58,59]. The role of SUBA-itraconazole in the treatment of histoplasmosis has been evaluated in a Mycoses Study Group trial and results have yet to be published.

Itraconazole levels should be measured after two weeks of therapy when the drug has reached steady state [47]. The dose should be adjusted to achieve a serum concentration of 1 to 2 mcg/mL, determined by adding together the itraconazole parent drug concentration and the hydroxy-itraconazole concentration measured by high-performance liquid chromatography (HPLC). If a bioassay is used, rather than HPLC, the levels are at least three times higher, and a concentration of 3 to 6 mcg/mL is recommended. The timing of the specimen following the dose is not critical because of itraconazole's long half-life. (See "Pharmacology of azoles", section on 'Itraconazole'.)

The factors that affect itraconazole pharmacokinetics, including drug interactions, absorption, and drug formulation, are discussed in detail separately (see "Pharmacology of azoles", section on 'Drug interactions'). Indications to repeat serum measurements include initially low values, dose modification, concern about compliance or absorption, initiation of treatment with potentially interacting medications, and suspicion of relapse.

FluconazoleFluconazole should be reserved for treatment of histoplasmosis in patients who cannot take itraconazole. The fluconazole dose should be at least 400 mg/day in immunocompetent individuals and 800 mg/day in patients with HIV or other immunocompromising conditions.

Fluconazole is not as active in vitro against H. capsulatum as itraconazole and has not been as effective when used for treatment [53,60], in part because fungemia is cleared more slowly [61]. In one study, 75 percent of patients with AIDS who had mild or moderately severe disease responded to fluconazole (800 mg/day); however, nearly one-third relapsed while receiving 400 mg/day as chronic maintenance therapy [60].

Another problem with fluconazole is the development of resistance [62]. In one report, one-half of Histoplasma strains from patients with AIDS who failed fluconazole therapy had developed in vitro resistance to the drug [62].

VoriconazoleVoriconazole, similar to fluconazole, is less active than itraconazole and posaconazole in vitro and, in some studies, was less effective [52,63]. It has been used successfully in a small number of patients with disseminated histoplasmosis, including those who had CNS infection and who failed or could not tolerate other therapy [48,52,55,64-68], but no clinical treatment trials have been conducted.

Posaconazole – Similar to itraconazole, H. capsulatum is highly susceptible to posaconazole [63]. No clinical treatment trials have been reported but this agent has been shown to be effective in individual case reports [48,69-72]. The extended-release tablet formulation achieves predictable serum concentrations and is often better tolerated than itraconazole.

IsavuconazoleIsavuconazole is active in vitro against H. capsulatum [73]. A few patients with histoplasmosis, including one with CNS infection, have been reported to have successful outcomes with isavuconazole [54,73].

EchinocandinsH. capsulatum is not susceptible to the echinocandins and they should not be used to treat this infection [74].

Drug interactions — All azoles are associated with a variety of drug interactions that may influence the choice of medication or dosing. These include drugs that can accelerate or impair the metabolism of an azole agent and drugs whose metabolism is slowed by the azoles. These issues are discussed in detail separately. (See "Pharmacology of azoles", section on 'Drug interactions' and "Itraconazole: Patient drug information" and "Fluconazole: Patient drug information".)

Monitoring response to therapy — Histoplasma antigen concentrations in the urine and serum fall with effective therapy and should be checked every few months during therapy and up to six months after completion of therapy to determine early signs of relapse [75]. Rising antigen values raise concern for relapse.

Reasons for treatment failure or relapse include: low itraconazole blood concentrations; poor adherence to medications; and resistance to antifungal agents, although the latter is uncommon. Patients who experience treatment failure or relapse should be managed in consultation with an infectious diseases provider experienced in the treatment of histoplasmosis.

Patients with CNS disease — For patients with central nervous system (CNS) histoplasmosis, aggressive therapy is recommended to achieve the greatest chance for a successful outcome. Treatment for Histoplasma meningitis is difficult because of the poor penetration of most antifungal agents into the CSF. In one older report, only 60 to 80 percent of patients with meningitis responded to treatment with amphotericin B, and up to one-half of responders relapsed during subsequent years [9].

Our general approach to treatment is described below. However, a clinician with experience in managing patients with CNS histoplasmosis should be consulted. Management may be particularly challenging in pregnant women, as azoles are contraindicated in the first trimester because of the risk of teratogenicity, and use later in pregnancy must balance possible risks with benefits.

Antimicrobial therapy – We administer liposomal amphotericin B (AmBisome, 5 mg/kg intravenously daily) for four to six weeks. A similar dose and duration of therapy is recommended if the lipid complex formulation (Abelcet) is used. Dose reduction or earlier transition to itraconazole may be needed in patients who develop renal impairment while taking amphotericin B.

Following induction therapy, itraconazole (200 mg orally twice or three times daily) should be given for at least one year to help prevent relapse. However, some clinicians will treat with an azole for life rather than stopping after one year, given the risk of relapse. Measurement of blood concentrations of itraconazole early in the course of therapy and at intervals throughout therapy is recommended to ensure adequate serum levels [35]. (See 'Antifungal agents' above.)

In patients unable to tolerate itraconazole, high-dose fluconazole (800 mg daily) is an alternative, as is voriconazole, which achieves excellent concentrations in the cerebrospinal fluid (CSF) [64,65,68]. The dose of voriconazole will depend on the serum concentrations achieved as well as the development of adverse effects. A reasonable starting dose would be 400 mg twice daily for one day followed by 200 mg twice daily. If concentrations of 2 to 5 mcg/mL are not achieved by day 5, the dose should be increased. Doses as high as 400 mg twice daily may be required.

This rationale for this approach is based on findings that liposomal amphotericin B (AmBisome) achieves higher concentrations in the brain than other lipid formulations or amphotericin B deoxycholate, providing a theoretical basis for its use in CNS histoplasmosis. Although fluconazole achieves excellent concentrations in the CSF [76], this agent was less effective than amphotericin B as monotherapy, and fluconazole plus amphotericin B was less effective than amphotericin B alone in an experimental model of Histoplasma meningitis [77]. Itraconazole, although more active than fluconazole against H. capsulatum, does not achieve measurable concentrations in the CSF [78]. However, this agent has been used successfully in the treatment of Histoplasma meningitis, as well as other fungal meningitides. Individual case reports have noted success with the other azoles in individual patients [64,65,68,69,73]. (See 'Antifungal agents' above.)

Administration of amphotericin B directly into the ventricles, cisterna magna, or lumbar arachnoid space is rarely, if ever, indicated; evidence is lacking for its effectiveness.

Monitoring – Patients with CNS histoplasmosis who respond to initial therapy should be followed closely for symptoms and signs of relapse of infection. Lumbar puncture should be repeated every few months to evaluate the patient's response to treatment; CSF studies include protein, glucose, white blood cell count, culture (if it was positive initially), and antigen tests. Laboratory testing should also include Histoplasma antigen from the serum and urine.

There are no data to guide the frequency of monitoring. If Histoplasma antigen tests were positive in urine or serum, we repeat these tests monthly for the first few months and then approximately every three months thereafter. A rise in serum or urine antigen level or reversion from negative to positive is worrisome for relapse, which is best evaluated by measuring the CSF antigen level. Additional information on monitoring is discussed above. (See 'Monitoring response to therapy' above.)

Relapse despite chronic suppressive therapy is an indication for repeat treatment with intravenous liposomal amphotericin B.

Concurrent immunosuppressive therapy — For patients taking immunosuppressive therapy at the time of histoplasmosis diagnosis, questions arise regarding how to manage the immunosuppressive agents.

Minimizing immunosuppression initially – For patients who develop disseminated histoplasmosis while taking immunosuppressive biologic agents, such as TNF-alpha inhibitors, the standard of practice is to stop the agent for at least several months to allow the patient to respond to the antifungal drug and control the infection [17]. For transplant recipients for whom immunosuppression cannot be stopped totally, minimizing the amount of immunosuppression as much as possible for at least several months should be the goal.

Restarting immunosuppressive therapy – The decision whether and when to start back on immunosuppressive therapy should be made together with the physician caring for the underlying disease that requires immunosuppression, the infectious diseases consultant, and the patient. Occasionally, an autoimmune disease may be under control and further immunosuppression may not be necessary. In other cases, another immunosuppressive agent with less conferred risk for disseminated histoplasmosis can be used instead. When the patient’s disease does require further immunosuppressive therapy with the same drug as before, we monitor closely with frequent visits and labs (eg, urine histoplasma antigen) to confirm continued response to antifungal drugs.

Duration of histoplasmosis therapy – For those who are at high risk for relapse of histoplasmosis because their immunosuppression cannot be reversed (eg, transplant recipients, ongoing use of a TNF-alpha inhibitor), long-term or lifelong maintenance therapy is reasonable [17,18,21,79]. Important points to consider in this decision are the extent of the histoplasmosis (eg, whether CNS infection is present, making relapse more likely); the response to antifungals (eg, has the antigen concentration fallen to undetectable and is the patient symptom-free); and the probability that the patient can be followed closely for signs of relapse after the antifungals are stopped over the ensuing months to years. For patients who remain on long-term or lifelong maintenance therapy, itraconazole is given at a dose of 200 mg once or twice daily.

Evidence to guide decision-making in these circumstances is scarce. There are no controlled trials to answer the above questions, and decisions must be made on a case-by-case basis.

Maintenance therapy in patients with HIV is discussed separately. (See "Treatment of histoplasmosis in patients with HIV", section on 'Maintenance therapy'.)

OUTCOMES — In the period before amphotericin B was introduced, disseminated histoplasmosis, whether acute or chronic, was fatal for all but a few patients [4,80]. Amphotericin B deoxycholate therapy changed the prognosis greatly, but relapses were common, primarily because long-term therapy with amphotericin B deoxycholate was extremely difficult [6]. Follow-up therapy of severe disseminated histoplasmosis and primary therapy of mild to moderate histoplasmosis with azole antifungal agents noted a continued decrease in mortality and prevented the occurrence of relapses [15,51,56,81,82]. Survival rates for patients with disseminated histoplasmosis now approach 90 percent. Patients with severe immune compromise have a worse prognosis, in general, but even in this population, the available treatment options ensure good outcomes in most patients [15,55,56,81].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Histoplasmosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topic (see "Patient education: Histoplasmosis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Spectrum of disease Histoplasmosis is the most prevalent endemic mycosis in the United States. Most infections are asymptomatic or self-limited, but some individuals develop acute pulmonary infection or severe disseminated disease. (See 'Introduction' above.)

Diagnosis

When to suspect disseminated histoplasmosis The diagnosis of disseminated histoplasmosis should be suspected in patients with risk factors for disease (eg, immunosuppression or extremes of age and risk factors for exposure) in combination with clinical manifestations that are consistent with disseminated histoplasmosis. (See 'When to suspect the diagnosis' above.)

Establishing the diagnosis Microscopic demonstration or isolation of Histoplasma from extrapulmonary sites provides proof of dissemination in patients with histoplasmosis. Histopathology using stains for fungi, cultures, antigen detection, and tests for Histoplasma-specific antibodies can all be used to help make the diagnosis. (See 'Establishing the diagnosis' above and 'Diagnostic methods' above.)

Diagnosis CNS histoplasmosis Establishing the diagnosis of meningitis due to histoplasmosis can be difficult; thus, for patients with suspected meningitis, cerebrospinal fluid (CSF), serum, and urine antigen testing, CSF and serum antibody testing, and CSF and blood cultures should be obtained (table 1). The diagnosis is often based upon detection of antigen or antibody in the CSF as CSF cultures are often not positive. (See 'Special considerations for diagnosing meningitis' above.)

Treatment Treatment is indicated for all patients with disseminated histoplasmosis. The natural history is progressive and fatal over a 2- to 12-week course in those with untreated acute disseminated infection, versus months to years in those with untreated chronic disseminated histoplasmosis. (See 'Indications' above.)

Histoplasmosis without CNS involvement For patients without central nervous system (CNS) involvement, the choice of agent depends primarily upon disease severity (table 2). (See 'Patients without CNS disease' above.)

-Severe disease For patients with severe disease (eg, those requiring hospitalization), one of the lipid formulations of amphotericin B should be initiated (eg, AmBisome at 3 mg/kg per day or Abelcet at 5 mg/kg per day). Itraconazole is not recommended for initial therapy in such patients since it does not eradicate fungemia as rapidly as amphotericin. However, most patients can be transitioned to oral itraconazole within one to two weeks.

-Mild to moderate disease For those with mild to moderate disease, itraconazole is the treatment of choice.

CNS histoplasmosis For patients with CNS histoplasmosis, we administer liposomal amphotericin B (AmBisome, 5 mg/kg intravenously daily) for four to six weeks. A similar dose and duration of therapy is recommended if the lipid complex formulation (Abelcet) is used. Following induction therapy, itraconazole (200 mg orally twice or three times daily) should be given for at least one year to prevent relapse. (See 'Patients with CNS disease' above.)

Duration – The total duration of treatment should be at least one year. Long-term or sometimes lifelong suppressive therapy is reasonable for those who are at risk for relapse of histoplasmosis because their immunosuppression cannot be reversed (eg, transplant recipients). (See 'Treatment' above.)

Monitoring response to therapyHistoplasma antigen concentrations in the urine and serum fall with effective therapy and should be monitored at regular intervals. Patients with CNS histoplasmosis also require monitoring of CSF. (See 'Monitoring response to therapy' above and 'Patients with CNS disease' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Joseph Wheat, MD, and Kieren Marr, MD, who contributed to an earlier version of this topic review.

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References

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