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Diagnosis and treatment of pulmonary histoplasmosis

Diagnosis and treatment of pulmonary histoplasmosis
Literature review current through: Jan 2024.
This topic last updated: Nov 15, 2023.

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].

The diagnosis and treatment of the various histoplasmosis pulmonary syndromes will be reviewed here. The pathogenesis and clinical features of these syndromes and issues regarding histoplasmosis in patients with human immunodeficiency virus (HIV) are discussed separately. (See "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Treatment of histoplasmosis in patients with HIV".)

WHEN TO SUSPECT HISTOPLASMOSIS — Pulmonary histoplasmosis should be considered in patients with the following clinical presentations, particularly in the appropriate epidemiologic setting:

Pneumonia with mediastinal or hilar lymphadenopathy

Mediastinal or hilar masses

Pulmonary nodule

Cavitary lung disease

Pericarditis with mediastinal lymphadenopathy

Pulmonary manifestations with arthritis or arthralgia plus erythema nodosum

Dysphagia caused by esophageal narrowing

Superior vena cava syndrome or obstruction of other mediastinal structures

These manifestations place pulmonary histoplasmosis in the differential diagnosis of sarcoidosis, tuberculosis, and malignancy [2]. Failure to exclude histoplasmosis in the evaluation of sarcoidosis may lead to marked disease exacerbation if immunosuppressive therapy is initiated in a patient who actually has acute histoplasmosis [3]. Similarly, failure to consider histoplasmosis in patients under evaluation for malignancy may lead to unnecessary surgical evaluation. Thus, in the appropriate epidemiologic setting, testing for histoplasmosis should be included for patients who are under evaluation for these conditions. (See 'Distinction from sarcoidosis' below.)

DIAGNOSIS — Histopathology using stains for fungi, cultures, antigen detection, and serologic tests for Histoplasma-specific antibodies can all help make the diagnosis of pulmonary histoplasmosis [4-6]. The characteristics of these tests vary in the different histoplasmosis syndromes, but all can serve as the basis for diagnosis in patients with compatible clinical findings. Each test has certain limitations that must be recognized if it is to be used correctly. Skin testing for histoplasmosis is not available.

Diagnostic methods — A general description of the various diagnostic methods for histoplasmosis follows. Decision-making regarding the use of individual assays within the context of varying clinical presentations is discussed below. (See 'Selection of diagnostic tests for different pulmonary syndromes' below.)

Histopathology and cytology — Morphologic findings in biopsy specimens include granulomas (in most cases), lymphohistiocytic aggregates, and diffuse mononuclear cell infiltrates (picture 1). Histopathologic examination of lung or mediastinal lymph node tissue using special stains that highlight fungi permits rapid diagnosis of histoplasmosis (picture 2) [7]. The sensitivity and specificity is decreased if pathologists are inexperienced in the recognition of H. capsulatum.

Yeast-phase organisms of H. capsulatum are ovoid in shape, measure 2 to 4 micron in diameter, and demonstrate narrow-based budding. Care must be taken in interpretation of fungal stains because Candida glabrata, Cryptococcus neoformans, Pneumocystis jirovecii, and staining artifacts may be misidentified as H. capsulatum.

Fungal cultures — Cultures are most useful in patients with chronic pulmonary histoplasmosis. Submission of multiple sputum or bronchoalveolar lavage (BAL) cultures produces a positive yield in the majority of cases [8]. In contrast, the sensitivity of respiratory cultures is much lower in localized disease or acute disease [9].

In addition to the low sensitivity of culture, the organism may not grow in culture for as long as six weeks; this delay in diagnosis may compromise care in a patient who is severely ill.

Antigen detection — Detection of antigen using the Histoplasma antigen detection enzyme immunoassay (EIA) in the urine, blood, or BAL fluid of infected patients provides rapid diagnostic information and is particularly useful in patients who are severely ill [4].

Most studies in the United States have been performed using an EIA developed at MiraVista Diagnostics. Using this assay, an H. capsulatum galactomannan can be detected in 60 to 83 percent of patients with acute pulmonary histoplasmosis, depending on the extent of the lung involvement [4,10]. The highest sensitivity is obtained by testing both urine and serum [11]. Another EIA developed by IMMY Laboratories uses a newly developed monoclonal antibody against H. capsulatum and has been used most extensively in Latin America in patients with HIV and disseminated histoplasmosis. In that population, this assay has similar sensitivity and specificity to the MiraVista assay for disseminated histoplasmosis, but this IMMY test has not been evaluated specifically in pulmonary histoplasmosis [12]. Similarly, a lateral flow assay, which has the advantage of being easily and quickly performed, has been developed by MiraVista Diagnostics, but is available only in Latin America and has been used for the diagnosis of disseminated histoplasmosis in patients with HIV and not for pulmonary histoplasmosis [13].

One study evaluated the utility of the Histoplasma antigen EIA on BAL fluid in the diagnosis of patients with pulmonary histoplasmosis, most of whom were immunocompromised and had diffuse disease; 29 of 31 patients with pulmonary histoplasmosis (94 percent) had positive antigen testing [7].

Cross-reactions are often seen in patients with blastomycosis [4], are seen less often in those with coccidioidomycosis, talaromycosis, and paracoccidioidomycosis [14], and are rarely seen in patients with aspergillosis [7]. Cross-reactions are not seen in patients infected with Candida or Cryptococcus [9].

Serology — Serologic testing is useful in the diagnosis of histoplasmosis in the patient with a compatible clinical presentation and epidemiologic risk factors (figure 1). Less than 1 percent of residents in endemic areas are seropositive by the immunodiffusion test and less than five percent have positive complement fixation assays; thus, background seropositivity is not a major limitation to serologic testing [15]. It should be noted that antibody assays may be falsely negative in immunosuppressed patients. In addition, in acute cases, antibodies usually appear during the second month after exposure and may thus be negative when first measured. Antibodies can remain positive for several years and thus may not indicate disease activity [15].

There are three available serologic tests: complement fixation, immunodiffusion, and enzyme immunoassay.

Complement fixation – The complement fixation test using antigens from the yeast and mycelial forms of H. capsulatum is slightly more sensitive, but less specific, than the immunodiffusion test. As an example, a serologic study of 276 patients during an urban outbreak of histoplasmosis found that complement fixation had a sensitivity of almost 95 percent versus 90 percent with immunodiffusion testing [15].

Complement fixation titers of 1:32 or higher are highly suggestive of acute infection, although titers of 1:8 or 1:16 should not be disregarded because titers in this range occur in about one-third of cases with active disease. However, positive results with the complement fixation test may represent a persistent antibody response from a previous episode of histoplasmosis or infection with other fungi (eg, coccidioidomycosis, blastomycosis). Positive results may also occur in patients with other granulomatous diseases (eg, sarcoidosis, tuberculosis) [16].

Immunodiffusion – The immunodiffusion test has greater specificity than the complement fixation test. In the immunodiffusion test, results are reported as M or H precipitins or bands. Most patients will develop an M band; the H precipitin band is detectable in fewer than 20 percent of cases. The H band is seen most often in patients who have disseminated infection, chronic cavitary pulmonary histoplasmosis, or more severe acute pulmonary histoplasmosis and is helpful for diagnosis when present. The M band becomes positive sooner than the H band and persists longer [17].

Enzyme immunoassay – An enzyme immunoassay (EIA) for antibodies against H. capsulatum has been available in some laboratories, but this method has not been found to be as sensitive as the complement fixation test. A more recently developed EIA for IgG and IgM antibodies to H. capsulatum could prove to be more sensitive. Using an EIA for IgG and IgM antibodies in combination with the H. capsulatum antigen assay proved to be more sensitive than immunodiffusion and/or complement fixation assays in one series of patients with acute pulmonary histoplasmosis [18].

Positive serologic antibody assays must be interpreted with caution in individuals who do not have clinical features that are suggestive of histoplasmosis. If the history is equivocal, documentation of infection with H. capsulatum by staining, culture, or antigen detection is highly desirable. On the other hand, serologic tests are often negative in immunosuppressed patients.

Polymerase chain reaction — The role of polymerase chain reaction (PCR) for diagnosis of histoplasmosis is uncertain. One study of a small number of tissue and respiratory samples found that 11 of 15 (73 percent) of culture-positive samples were positive by PCR [19]. In another report, PCR was positive only if organisms were seen by microscopy [20]. A newer, nested real-time PCR assay was noted to have a sensitivity of 77 percent in a small number of clinical samples (serum, tissue, BAL) [21,22].

Distinction from sarcoidosis — The clinical and radiographic findings in pulmonary histoplasmosis may be similar to those seen with sarcoidosis [16,23]. Shared findings include diffuse pulmonary infiltrates, mediastinal lymphadenopathy, erythema nodosum, hepatic enzyme elevation, and splenomegaly. Elevated serum angiotensin converting enzyme concentrations and noncaseating granulomas can be seen in both conditions [16,24]. (See "Clinical manifestations and diagnosis of sarcoidosis".)

Histoplasmosis must be excluded before treating patients with presumed sarcoidosis with immunosuppressive medications. A mistake in diagnosis can be disastrous if the patient is treated with corticosteroids or other immunosuppressive medications [3]. Although patients may appear to improve transiently, they eventually experience progressive disease that will result in increased morbidity and mortality if the true diagnosis is not identified [16,25-27]. (See 'Antigen detection' above and "Clinical manifestations and diagnosis of sarcoidosis" and "Treatment of pulmonary sarcoidosis: Initial approach".)

The evaluation should include the following in most patients:

Antigen testing of urine, serum, and BAL fluid.

Fungal culture of BAL fluid or other respiratory secretions.

Cytology or histopathology of respiratory specimens or lung tissue examined by an experienced pathologist.

Antibody testing of serum by immunodiffusion, complement fixation, and EIA, if available.

Positive results suggesting active histoplasmosis precludes immunosuppressive therapy, but negative results do not entirely exclude histoplasmosis. In such patients, the response to immunosuppressive therapy must be carefully monitored, including repeat antigen and antibody testing.

Selection of diagnostic tests for different pulmonary syndromes — The yield of the diagnostic modalities differs depending upon the extent of the infection and timing following exposure. A battery of tests is required to achieve the highest sensitivity for diagnosis. Antigen tests and serology may be negative when first performed, but become positive later as the illness progresses. Thus, follow-up testing is encouraged in a patient with progressive illness if the first tests are negative.

Acute diffuse pulmonary disease — The fungal burden is often high in patients with diffuse infiltrates presenting within a month following exposure to a high inoculum of conidia. In such cases, antigen and antibody testing provide the highest sensitivity [28]. Antibodies may be negative initially but positive several weeks later.

Bronchoscopy or lung biopsy may be needed to establish the diagnosis in some cases when less invasive testing is not diagnostic or the illness is too severe to wait for results of antigen or antibody tests.

Acute localized pulmonary disease — The fungal burden is generally lower in patients presenting with symptoms of more than one month in duration accompanied by localized pulmonary infiltrates and/or mediastinal lymphadenopathy, and usually without a recognized exposure. Antigen may be detected in the urine or serum in only 40 percent of cases [4]. Cultures and pathology of respiratory specimens or lung may be positive in some cases. Antigen testing of bronchoalveolar lavage (BAL) fluid may improve the sensitivity over culture alone [7]. Serological tests for antibodies are positive in over 90 percent of cases if both the immunodiffusion and complement fixation tests are performed

Chronic cavitary pulmonary histoplasmosis — Serology is positive in most cases, and the complement fixation titers are often high. Most patients are able to expectorate sputum, but some may require bronchoscopy to obtain adequate specimens. If sputum cannot be obtained, cultures are negative, complement fixation titers are low (1:8 or 1:16), or if another diagnosis is suspected (eg, lung cancer or mycobacterial infection), bronchoscopy should be performed. Cultures of sputum or bronchoscopy specimens have been reported to be positive in 65 to 85 percent of cases [29]. Antigen detection in serum and urine may yield positive results and also should be performed on BAL fluid if available [4,7].

Lung biopsy is rarely needed and should be avoided in this population with obstructive lung disease because of the risk for surgical complications, including pneumothorax and bronchopleural fistula.

Mediastinal syndromes, broncholithiasis, and lung nodules — Few, if any, viable organisms persist in the tissues of patients with these manifestations of histoplasmosis, which represent complications of or expected sequelae of the healing process. Thus, cultures and antigen tests are usually negative, even though stains for fungi on the tissues may show organisms consistent with H. capsulatum [5,6,30-32]. Organisms can often be seen in pulmonary nodules, but cultures and test for antigens are negative; antibodies may be detected in low titers of 1:8 or 1:16 by complement fixation in a few cases. One study reported that detection of antibodies to H. capsulatum may aid in differentiating malignancy and histoplasmosis in children with mediastinal masses [33].

One indication for surgery in these situations is to exclude malignancy in patients with noncalcified pulmonary nodules or mediastinal lymphadenopathy [34]. Another indication for surgery is if extrinsic compression of mediastinal structures from enlarged lymph nodes occurs. In patients without risk factors for malignancy, follow-up with computed tomography scan at three-to-six-month intervals for one to two years is a reasonable approach. Surgery should not be performed for diagnosis of fibrosing mediastinitis because serious complications often occur [30]. (See "Mediastinal granuloma and fibrosing mediastinitis".)

TREATMENT — The optimal treatment for histoplasmosis varies according to the patient's clinical syndrome (table 1). Most infections caused by H. capsulatum are self-limited and require no therapy. However, patients who are exposed to a large inoculum of Histoplasma and those who are immunocompromised usually require antifungal treatment because they are more likely to develop severe disease. Itraconazole, fluconazole, voriconazole, posaconazole, isavuconazole, and amphotericin B all have in vitro activity against H. capsulatum, but clinical trials have only been conducted with itraconazole, fluconazole, and amphotericin B. Itraconazole is generally preferred for mild to moderate histoplasmosis, and amphotericin B has a role in the treatment of moderately severe and severe infections [35].

Antifungal agents

Amphotericin B — Because of its potential toxicity, amphotericin B is reserved for the initial treatment of patients who have moderately severe or severe infection. (See "Amphotericin B nephrotoxicity".)

Lipid preparations of amphotericin B are generally preferred because of reduced nephrotoxicity associated with their use (table 1). In addition, a more rapid response to treatment and improved survival have been noted with liposomal amphotericin B (AmBisome) when compared with amphotericin B deoxycholate in patients with AIDS and disseminated histoplasmosis [36]. However, amphotericin B deoxycholate can be used if lipid formulations are not available [35].

Itraconazole — Itraconazole is highly active against H. capsulatum. In a Mycoses Study Group trial of patients with pulmonary histoplasmosis, cure was achieved in 81 percent of cases [37].

Oral therapy with itraconazole is appropriate for patients with mild to moderate histoplasmosis and for continuation of outpatient therapy in those initially treated with amphotericin B. Itraconazole should be administered as a loading dose (200 mg orally three times daily for three days) in order to more rapidly achieve therapeutic serum concentrations followed by 200 mg once or twice daily, depending upon the serum drug concentrations [35].

Itraconazole serum concentrations should be measured after two weeks of therapy, when the drug has reached steady state [35]. It is recommended that the measured serum itraconazole concentration be at least 1 mcg/mL by high-performance liquid chromatography (HPLC) and 3 mcg/mL by bioassay [35]; however, levels of at least 2 mcg/mL by HPLC are preferred by some clinicians. The timing of the blood collection following the dose is not critical because of itraconazole's long half-life. Additional discussions of serum drug monitoring, as well as factors that affect itraconazole pharmacokinetics (eg, drug interactions, absorption, and drug formulation), are found elsewhere. (See "Pharmacology of azoles", section on 'Itraconazole' and "Pharmacology of azoles", section on 'Drug interactions'.)

Fluconazole — Fluconazole is well tolerated and is available in both oral and intravenous preparations. However, fluconazole is not as active against H. capsulatum in vitro and has produced less favorable results than itraconazole in clinical trials [38]. In a Mycoses Study Group trial, fluconazole led to clinical improvement in only 54 percent of cases of pulmonary histoplasmosis [38]. Furthermore, the development of resistance to fluconazole has been reported in patients with HIV [39].

In summary, fluconazole is not recommended as a standard treatment for histoplasmosis and should only be used in patients who cannot tolerate itraconazole or who cannot achieve adequate blood levels [35]. Patients who are treated with fluconazole for histoplasmosis should be monitored carefully for relapse. The recommended dosage is 400 to 800 mg daily.

Posaconazole — H. capsulatum is highly susceptible in vitro to posaconazole and has been used successfully as salvage therapy in patients who had failed other regimens [40].

Voriconazole — Voriconazole is active in vitro against H. capsulatum and has been shown to be effective in a small number of patients with histoplasmosis [41,42].

Isavuconazole — Isavuconazole is active in vitro against H. capsulatum, but very few patients who were treated with this agent have been reported [43].

Echinocandins — H. capsulatum does not appear to be susceptible to the echinocandins in vitro and these agents have been ineffective in a murine model [4]. They should not be used to treat histoplasmosis.

Approach to treatment — Clinical practice guidelines for the management of patients with histoplasmosis were published in 2007 by the Infectious Diseases Society of America (IDSA) and are undergoing revision [35]. The therapeutic approach to pulmonary histoplasmosis varies according to the specific disease process (table 1) [35]. Considerations in pregnancy are discussed below. (See 'Considerations in pregnancy' below.)

Acute diffuse pulmonary histoplasmosis

Moderately severe to severe disease — Patients with severe dyspnea and hypoxemia and/or development of acute respiratory distress syndrome (ARDS) should be treated initially with amphotericin B. The addition of methylprednisolone (0.5 to 1.0 mg/kg/d intravenously) for one to two weeks has been used in some patients with clinical benefit; the IDSA guidelines for treatment of histoplasmosis suggest that corticosteroids be considered for severe acute pulmonary histoplasmosis [35].

Amphotericin B should be dosed as follows (see 'Amphotericin B' above):

Liposomal amphotericin B (AmBisome) – 3 mg/kg/day intravenously

Amphotericin B lipid complex (Abelcet) – 5 mg/kg/day intravenously

Amphotericin B deoxycholate – 0.7 to 1 mg/kg/day intravenously

In general, one to two weeks of amphotericin B are usually required, and should be followed by itraconazole (200 mg orally three times daily for the first three days, then 200 mg orally twice daily) for a minimum of 12 weeks. Some patients respond more slowly, and treatment with itraconazole should be continued until patients are asymptomatic and radiographic evidence of pneumonia has resolved. This may require up to an additional three months of itraconazole therapy.

Mild to moderate disease — Treatment is generally not required for patients with mild to moderate disease if they have had symptoms for <4 weeks. However, therapy should be initiated if patients have symptoms extending beyond that period of time (table 1) [35].

If treatment is indicated, itraconazole can be used as initial therapy. Itraconazole should be given as a loading dose (200 mg orally three times daily for the first three days) followed by a maintenance dose (200 mg orally once or twice daily) for 6 to 12 weeks [35]. Antifungal therapy can be discontinued when pulmonary infiltrates have resolved [35].

Acute localized pulmonary disease — Therapy with itraconazole should be considered in symptomatic patients who present with localized infiltrates and/or mediastinal lymphadenopathy and show no improvement after four weeks of symptoms. Whether therapy alters the course in such cases is unknown.

Chronic cavitary pulmonary histoplasmosis — Treatment is indicated in all patients with chronic pulmonary histoplasmosis because the infection results in progressive loss of pulmonary function in most patients and death in as many as 30 percent of cases [29]. Most patients can be treated with oral itraconazole and do not require amphotericin B therapy.

Itraconazole should be given as a loading dose (200 mg orally three times daily for the first three days) followed by a maintenance dose (200 mg orally once or twice daily) for at least one year. Some experts prefer 18 to 24 months of antifungal therapy given the substantial risk of relapse [35]. Early studies found that amphotericin B could halt disease progression and significantly reduce mortality [44], and subsequent studies have shown the efficacy of itraconazole [37].

Radiographic abnormalities improve during the first year of treatment in at least two-thirds of cases but often do not resolve completely. Treatment should not be discontinued until radiographic findings have stabilized.

Serum and urine Histoplasma antigen tests may be negative in patients with chronic pulmonary histoplasmosis. Antibody titers should not be used to gauge the response to therapy because antibodies to H. capsulatum may persist despite clinical improvement.

Vigilance for relapse must be maintained after treatment is stopped because as many as 10 to 20 percent of patients with chronic pulmonary histoplasmosis may experience a relapse. Chest radiographs should be obtained every six months for the first year after treatment is discontinued and then annually or with the recurrence of symptoms to exclude reactivation. Most relapses occur within two years of stopping therapy.

Mediastinal granuloma and mediastinal lymphadenitis — Generally, treatment with antifungal agents is not indicated for these two complications of pulmonary histoplasmosis because active infection is no longer present. However, for patients who have symptoms associated with compression of adjacent structures, itraconazole frequently is prescribed, but there are no clinical trials that show this is effective [6,35]. Glucocorticoids are sometimes added in children especially when symptoms suggesting respiratory compromise occur [32].

Surgical resection of obstructive masses should be considered for patients with mediastinal granuloma who have symptoms related to compression of adjacent structures or in whom a fistula to adjacent structures with drainage of necrotic material has occurred [5,6,30]. Excision is not indicated to prevent subsequent fibrosing mediastinitis because these two disease processes are not related.

Fibrosing mediastinitis — Fibrosing mediastinitis is a rare progressive fibrotic condition, which causes significant disability and death in some patients who have bilateral involvement but can be milder and less disabling in those who have unilateral disease. Newer studies show better outcomes than older ones [31] (see "Mediastinal granuloma and fibrosing mediastinitis"). Large prospective studies with long-term follow-up have not been conducted, and predicting outcome in individual cases is difficult. Most authorities believe that neither antifungal nor anti-inflammatory treatment improves the outcome of this complication of histoplasmosis [30,34,35,45].

In patients with symptoms of obstruction of pulmonary arteries or veins, stent placement has been used successfully [46,47]. In one study in which stenting was evaluated, major complications requiring immediate surgery occurred in 10 percent of cases, and one patient died following pulmonary vein angioplasty [47]. Placement of stents in the airways is discouraged for patients with histoplasmosis, since granulation tissue often invades the stent causing further obstruction of the airways, and airway stents may be difficult to remove should obstruction develop.

Surgery should be discouraged because of high operative mortality rates and limited benefit. As an example, one review of 71 patients with fibrosing mediastinitis who had occlusion of the major central airways or major vessels found that only 40 percent benefited and 20 percent died as a result of surgery [30].

Referral of patients with this condition to clinicians who are experienced with its management should be strongly encouraged in view of the poor prognosis and uncertainty of current treatment recommendations.

Broncholithiasis — If removal is necessary, bronchoscopy is generally the procedure used unless massive hemoptysis or fistula formation has occurred [48,49]. Antifungal therapy is not indicated. (See "Pathogenesis and clinical features of pulmonary histoplasmosis", section on 'Broncholithiasis'.)

Pulmonary nodules (histoplasmomas) — Sites of healed Histoplasma lung infection can evolve into pulmonary nodules that can persist long term [35,50]. They are typically asymptomatic and may be identified incidentally on chest x-rays or computed tomography (CT) imaging. In the setting of one or a few isolated nodules, there is no evidence that antifungal therapy is beneficial [35]. This should be differentiated from symptomatic patients who have multiple or diffuse nodules and who require treatment for acute pulmonary histoplasmosis [35]. (See 'Acute diffuse pulmonary histoplasmosis' above.)

Considerations in pregnancy — Pregnant patients with histoplasmosis should be managed in conjunction with an expert in infectious diseases. Such patients typically require treatment with amphotericin B, since azoles are teratogenic, particularly in the first trimester.

EXTRAPULMONARY MANIFESTATIONS — Extrapulmonary manifestations of histoplasmosis include pericarditis and rheumatologic manifestations, which are caused by the inflammatory response to H. capsulatum rather than infection, per se. Symptomatic patients recover with anti-inflammatory drugs alone. In two large series of 45 patients with pericarditis [51,52] and 24 patients with arthritis [53], 67 of 69 patients recovered with anti-inflammatory treatment alone, while two patients recovered following combination therapy with an anti-inflammatory agent and an antifungal agent. We typically use a nonsteroidal anti-inflammatory drug; prednisone (60 mg/day) is reserved for patients who fail to respond to nonsteroidal agents. Patients who have pericardial effusions causing hemodynamic compromise must have drainage of the pericardial fluid.

Rare cases of disseminated histoplasmosis with involvement of the pericardium or joints must not be confused with these inflammatory syndromes; aggressive antifungal therapy is required in patients with disseminated disease. (See "Diagnosis and treatment of disseminated histoplasmosis in patients without HIV".)

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

Clinical epidemiology and spectrum of disease − 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. (See 'Introduction' above.)

When to suspect histoplasmosis − Pulmonary histoplasmosis should be considered in patients with the following clinical presentations, particularly in the appropriate epidemiologic setting:

Pneumonia with mediastinal or hilar lymphadenopathy

Mediastinal or hilar masses

Pulmonary nodule

Cavitary lung disease

Pericarditis with mediastinal lymphadenopathy

Pulmonary manifestations with arthritis or arthralgia plus erythema nodosum

Dysphagia caused by esophageal narrowing

Superior vena cava syndrome or obstruction of other mediastinal structures. These manifestations place pulmonary histoplasmosis in the differential diagnosis of sarcoidosis, tuberculosis, and malignancy. (See 'When to suspect histoplasmosis' above.)

Diagnosis − Histopathology using stains for fungi, cultures, antigen detection, and serologic tests for Histoplasma-specific antibodies can all help make a diagnosis of pulmonary histoplasmosis. (See 'Diagnosis' above.)

Diagnostic methods − The yield of the diagnostic modalities differs depending upon the extent of the infection and timing following exposure. A battery of tests is required to achieve the highest sensitivity for diagnosis. Antigen tests and serology may be negative when first performed but become positive later as the illness progresses. (See 'Diagnostic methods' above.)

Distinguishing histoplasmosis from sarcoidosis − The clinical and radiographic findings in pulmonary histoplasmosis and sarcoidosis may be similar. A mistake in diagnosis can be disastrous if the patient is treated with corticosteroids or other immunosuppressive medications. As a result, histoplasmosis must be excluded before treating patients with presumed sarcoidosis with immunosuppressive medications. (See 'Distinction from sarcoidosis' above.)

Treatment − The optimal treatment for histoplasmosis varies according to the patient's clinical syndrome (table 1). Most infections caused by H. capsulatum are self-limited and require no therapy. However, patients who are exposed to a large inoculum of Histoplasma and those who are immunocompromised usually require antifungal therapy. (See 'Treatment' above.)

For patients with moderately severe to severe acute pulmonary infection, initial therapy with amphotericin B is indicated. After one to two weeks, patients can be transitioned to itraconazole for a total duration of three to six months. (See 'Moderately severe to severe disease' above.)

For patients with mild to moderate symptoms of acute pulmonary infection that have been present for <4 weeks, treatment is usually not needed. However, if symptoms extend beyond that period of time, itraconazole should be administered for 6 to 12 weeks. (See 'Mild to moderate disease' above and 'Acute localized pulmonary disease' above.)

Treatment is indicated in all patients with chronic pulmonary histoplasmosis because the infection results in progressive loss of pulmonary function in most patients, and death in as many as 30 percent of cases. (See 'Chronic cavitary pulmonary histoplasmosis' above.)

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

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Topic 2451 Version 33.0

References

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