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Official reprint from UpToDate


www.uptodate.com 2015 UpToDate

Diagnosis and treatment of pulmonary histoplasmosis


Authors
Joseph Wheat, MD
Carol A Kauffman, MD

Section Editor
Kieren A Marr, MD

Deputy Editor
Jennifer Mitty, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2015. | This topic last updated: May 15, 2015.
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 HIV-infected patients are
discussed separately. (See "Pathogenesis and clinical features of pulmonary histoplasmosis" and "Diagnosis and
treatment of histoplasmosis in HIV-infected patients".)
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 Histoplasmaspecific antibodies can all help make the diagnosis of pulmonary histoplasmosis [4]. 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. The materials for
histoplasmin skin testing are no longer available.
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

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2) [5]. 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 cultures produces a positive yield in the majority of cases [6]. In contrast, the
sensitivity of respiratory cultures is much lower in localized disease or acute disease [7].
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 bronchoalveolar lavage fluid of infected patients provides rapid diagnostic information and is particularly
useful in patients who are severely ill [4].
Most studies have been performed using a commercial test that is currently available in the United States. In these
studies, 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 [4,8]. The highest sensitivity is obtained by testing both
urine and serum [9]. Other tests have been developed using different antibodies [10-14].
One study evaluated the utility of the Histoplasma antigen EIA on bronchoalveolar lavage 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 [5].
Cross-reactions can be seen in patients with blastomycosis [4], coccidioidomycosis, penicilliosis (due to Penicillium
marneffei), paracoccidioidomycosis, and African histoplasmosis [15], and also rarely in aspergillosis [5], but not in
patients infected with Candida or Cryptococcus [7].
Please note that one of the authors (JW) is owner and Director of MiraVista Diagnostics, one of several
companies that performs the Histoplasma antigen EIA.
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 [16]. It should be noted that antibody assays
may be falsely negative in immunosuppressed patients. 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 [16].
Comparison of serologic methods The complement fixation test using antigens from the yeast and mycelial
forms of H. capsulatum is slightly more sensitive than the immunodiffusion test. As an example, 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 [16]. Complement fixation titers of 1:32 or higher are highly
suggestive of acute infection, but 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, the immunodiffusion test has greater specificity than the complement fixation test. 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); the cause of this is uncertain [17]. Of note is that active
histoplasmosis should be excluded before making a diagnosis of sarcoidosis and should be considered in patients
presumed to have tuberculosis in which mycobacterial cultures and stains are negative. (See 'Distinction from
sarcoidosis' below.)

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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 [18].
Some laboratories use an enzyme immunoassay as a screening serology for histoplasmosis. The enzyme
immunoassay methods, however, have not been shown to be as sensitive as the complement fixation test, and may be
falsely negative in patients with histoplasmosis. Furthermore, background seropositivity and cross reactivity in other
endemic mycoses may be higher using enzyme immunoassay methods.
In summary, positive serologic 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 culturepositive samples were positive by PCR [19]. In another report, PCR was positive only if organisms were seen by
microscopy [20]. Other studies noted a sensitivity of 8 percent of urine and 22 percent of bronchoalveolar lavage
(BAL) specimens that were positive for Histoplasma antigen, whereas results in cerebrospinal fluid (CSF) and serum
were uniformly negative [8,21].
Distinction 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 [3]. Although such patients may appear to improve transiently, they eventually
experience progressive disseminated disease, which may result in increased morbidity and mortality if the true
diagnosis is not identified. If there is a high suspicion for histoplasmosis (eg, a patient who has resided in an endemic
area with clinical features that are suggestive of histoplasmosis), a tissue diagnosis should be pursued before initiating
glucocorticoids, especially if the Histoplasma antigen test on urine and serum is negative. If initial antibody tests are
negative, repeat testing is recommended before initiating glucocorticoid treatment, since seroconversion may occur.
Antigen testing should be repeated following initiation of glucocorticoid therapy because progressive dissemination may
occur if the patient has histoplasmosis rather than sarcoidosis. If bronchoscopy is performed, bronchoalveolar fluid
also should be tested for antigen. (See 'Antigen detection' above and "Clinical manifestations and diagnosis of
pulmonary sarcoidosis" and "Treatment of pulmonary sarcoidosis with glucocorticoids".)
As a result, histoplasmosis must be excluded before treating patients with presumed sarcoidosis with
immunosuppressive medications, particularly in endemic areas. The evaluation should include the following:
Antigen testing of urine, serum, and bronchoalveolar lavage fluid
Fungal culture of bronchoalveolar lavage 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 and complement fixation
Positive results suggesting active histoplasmosis would preclude immunosuppressive therapy, but negative results
would not entirely exclude histoplasmosis. In such patients, the response to immunosuppressive therapy must be
carefully monitored, including repeat antigen 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.

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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. Antibodies may be negative initially but positive a month 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 test. In such cases, pathology and/or
culture are positive in about 40 percent of patients.
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 fluid may improve the sensitivity over culture alone [5]. 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 [22]. Antigen was detected in the urine in seven of eight of cases [4] and, in bronchoscopy specimens, in five
other patients who had negative antigen results in urine [5].
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 as well as bacterial superinfection.
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 [2]. Thus, cultures and antigen tests are usually negative, even though stains for fungi on the tissues
may show organisms consistent with H. capsulatum [23]. In a review of fibrosing mediastinitis, evidence for prior
infection with H. capsulatum was obtained by positive antibody tests in 17 of 58 (29 percent) patients who had these
assays performed, and organisms compatible with H. capsulatum were seen in 11 of 43 (26 percent) biopsy
specimens [24]. Tests for antigen are expected to be negative in most cases.
Organisms can often be seen in pulmonary nodules, but cultures and test for antigens are negative, and antibodies
may be detected in low titers of 1:8 or 1:16 by complement fixation in some cases.
The main indication for surgery in these situations is to exclude malignancy in patients with noncalcified pulmonary
nodules or mediastinal lymphadenopathy [25]. In patients without risk factors for malignancy, follow-up with computed
tomography (CT) scan at three to six month intervals for one to two years is a reasonable approach. Surgery should
rarely be required for diagnosis of fibrosing mediastinitis because the clinical syndrome is unique and surgery may
cause serious and avoidable complications [23]. (See "Fibrosing mediastinitis".)
ANTIFUNGAL THERAPY Clinical practice guidelines for the management of patients with histoplasmosis were
updated in 2007 by the Infectious Diseases Society of America [26].
General approach 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.
Itraconazole, fluconazole, voriconazole, posaconazole, 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 [26].

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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. 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 who have AIDS and
disseminated histoplasmosis [27]. However, the use of amphotericin B deoxycholate may be considered in patients
without risk factors for renal insufficiency due to its lower cost [26].
Dosing of the various amphotericin B preparations is as follows:
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
Patients often respond to amphotericin B within a few days and then can be switched to itraconazole to finish the
course of therapy [26]. (See "Pharmacology of amphotericin B".)
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 [28].
Oral therapy with itraconazole is appropriate for patients not requiring hospitalization 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 rapidly achieve therapeutic serum concentrations followed by 200 mg
once or twice daily, depending upon the serum drug concentrations [26].
Itraconazole levels should be measured after two weeks of therapy so that the drug has reached steady state [26].
The dose should be adjusted to achieve a serum concentration of 1 to 2 mcg/mL for the sum of the itraconazole parent
drug and the hydroxyl metabolite by high-performance liquid chromatography (HPLC). If a bioassay is used, 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'.)
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 [29]. In a Mycoses Study Group trial, fluconazole led to clinical improvement in only 54 percent of cases
of pulmonary histoplasmosis [29]. Furthermore, the development of resistance to fluconazole has been reported in
AIDS patients [30].
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 [26]. 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 [31].
Voriconazole Voriconazole is active in vitro against H. capsulatum and has been shown to be effective in a small
number of patients with histoplasmosis [32,33].
Echinocandins H. capsulatum does not appear to be susceptible to the echinocandins in vitro and they have been
ineffective in a murine model [4].

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THERAPY FOR PULMONARY HISTOPLASMOSIS Clinical practice guidelines for the management of patients with
histoplasmosis were updated in 2007 by the Infectious Diseases Society of America (IDSA) [26]. The therapeutic
approach to pulmonary histoplasmosis varies according to the specific disease process (table 1) [26].
Acute diffuse pulmonary histoplasmosis Therapy is indicated in most patients with diffuse pulmonary infiltrates
who present within a month of exposure to a large inoculum of H. capsulatum and in all patients who have moderately
severe or severe disease. Patients with 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 and is recommended
in the IDSA guidelines [26]. Amphotericin B should be dosed as follows:
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
(See 'Amphotericin B' above.)
Clinical improvement is often dramatic and may occur within several days of therapy, permitting rapid transition to
itraconazole to complete a twelve week course of therapy.
Itraconazole can be used as initial therapy in patients who are not sufficiently ill to require hospitalization (ie, mild to
moderate pulmonary histoplasmosis) but who have persistent symptoms for >1 month [26]. 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 six to twelve weeks [26]. Antifungal therapy can be discontinued when pulmonary
infiltrates have resolved [26].
Acute localized pulmonary disease Therapy 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 [22].
Amphotericin B can halt disease progression and significantly reduces mortality [34]. Subsequent studies have shown
the efficacy of itraconazole therapy [28]. 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 [26].
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 improvement has ceased.
Serum and urine Histoplasma antigen tests are often 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. While most relapses occur within two years of
stopping therapy, follow-up should be continued for at least five years. 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.
Granulomatous mediastinitis The course of untreated granulomatous mediastinitis is unpredictable, and its
response to treatment has been difficult to assess objectively. Treatment is not indicated in asymptomatic patients in
whom the findings may resolve without treatment. For symptomatic patients, itraconazole (200 mg orally three times

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daily for three days, followed by 200 mg orally once or twice daily) for 6 to 12 weeks is recommended, although there
are no controlled trials to prove its efficacy [26].
Surgical resection of obstructive masses can be considered and is generally safe for patients whose symptoms do not
improve after one to three months of antifungal therapy [23]. Of 27 cases undergoing resection of mediastinal nodes,
lobectomy, or esophageal repair, only one experienced a complication [35]. Excision is not indicated to prevent
subsequent fibrosing mediastinitis because these two disease processes are not related [23].
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 [24]. The approach to therapy is
described in detail elsewhere [23,25,26,36] and will be briefly reviewed here (see "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 antiinflammatory treatment improves the outcome of this
complication of histoplasmosis [23,25,26,36].
In patients with symptoms of obstruction of pulmonary arteries or veins, stent placement has been used successfully
[37,38]. 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 [38]. 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 [23].
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 Calcified lymph nodes (broncholiths) rarely erode into adjacent bronchi, which can cause
symptoms of hemoptysis and expectoration of tiny calcified particles. Lobectomy or transbronchial removal for relief of
obstruction was effective in 13 cases, but complications of air leak and empyema occurred in one patient each [35].
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 [26,39]. 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 [26]. However, symptomatic patients who have multiple or diffuse nodules may benefit
from treatment if the findings are suggestive of acute pulmonary histoplasmosis [26]. (See 'Acute diffuse pulmonary
histoplasmosis' above.)
EXTRAPULMONARY MANIFESTATIONS
Pericarditis or rheumatologic syndromes Pericarditis and rheumatologic manifestations are caused by the
inflammatory response to H. capsulatum rather than infection, per se. However, patients may or may not exhibit
pulmonary manifestations. Symptomatic patients recover with antiinflammatory drugs alone. In two large series of 45
patients with pericarditis [40,41] and 24 patients with arthritis [42], 67 of 69 patients recovered with antiinflammatory
treatment alone, while two patients recovered following combination therapy with an antiinflammatory agent and an
antifungal agent. We typically use a nonsteroidal antiinflammatory 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

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"Diagnosis and treatment of disseminated histoplasmosis in non-HIV-infected patients".)


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 information: Histoplasmosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
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.)
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.)
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.)
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.)
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
'Selection of diagnostic tests for different pulmonary syndromes' above.)
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.

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(See 'General approach' above.)


Itraconazole is generally preferred for mild to moderate histoplasmosis, and amphotericin B for the treatment of
moderately severe to severe infections. (See 'General approach' above.)
Therapy should be considered in patients with more than four weeks of symptoms but may not be indicated in
those with mild symptoms who are already improving. Therapy is indicated without delay in patients with
moderately severe or severe disease. (See 'Acute diffuse pulmonary histoplasmosis' 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.)
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REFERENCES
1. Chu JH, Feudtner C, Heydon K, et al. Hospitalizations for endemic mycoses: a population-based national study.
Clin Infect Dis 2006; 42:822.
2. Wheat LJ, Conces D, Allen SD, et al. Pulmonary histoplasmosis syndromes: recognition, diagnosis, and
management. Semin Respir Crit Care Med 2004; 25:129.
3. Gulati M, Saint S, Tierney LM Jr. Clinical problem-solving. Impatient inpatient care. N Engl J Med 2000; 342:37.
4. Hage CA, Ribes JA, Wengenack NL, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin
Infect Dis 2011; 53:448.
5. Hage CA, Davis TE, Fuller D, et al. Diagnosis of histoplasmosis by antigen detection in BAL fluid. Chest 2010;
137:623.
6. Wheat LJ, Wass J, Norton J, et al. Cavitary histoplasmosis occurring during two large urban outbreaks. Analysis
of clinical, epidemiologic, roentgenographic, and laboratory features. Medicine (Baltimore) 1984; 63:201.
7. Wheat LJ. Approach to the diagnosis of the endemic mycoses. Clin Chest Med 2009; 30:379.
8. Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther 2006; 6:1207.
9. Swartzentruber S, Rhodes L, Kurkjian K, et al. Diagnosis of acute pulmonary histoplasmosis by antigen
detection. Clin Infect Dis 2009; 49:1878.
10. Lindsley MD, Holland HL, Bragg SL, et al. Production and evaluation of reagents for detection of Histoplasma
capsulatum antigenuria by enzyme immunoassay. Clin Vaccine Immunol 2007; 14:700.
11. Scheel CM, Samayoa B, Herrera A, et al. Development and evaluation of an enzyme-linked immunosorbent
assay to detect Histoplasma capsulatum antigenuria in immunocompromised patients. Clin Vaccine Immunol
2009; 16:852.
12. Cloud JL, Bauman SK, Neary BP, et al. Performance characteristics of a polyclonal enzyme immunoassay for the
quantitation of Histoplasma antigen in human urine samples. Am J Clin Pathol 2007; 128:18.
13. Theel ES, Harring JA, Dababneh AS, et al. Reevaluation of commercial reagents for detection of Histoplasma
capsulatum antigen in urine. J Clin Microbiol 2015; 53:1198.
14. Theel ES, Jespersen DJ, Harring J, et al. Evaluation of an enzyme immunoassay for detection of Histoplasma
capsulatum antigen from urine specimens. J Clin Microbiol 2013; 51:3555.
15. Wheat J, Wheat H, Connolly P, et al. Cross-reactivity in Histoplasma capsulatum variety capsulatum antigen
assays of urine samples from patients with endemic mycoses. Clin Infect Dis 1997; 24:1169.
16. Wheat J, French ML, Kohler RB, et al. The diagnostic laboratory tests for histoplasmosis: analysis of experience
in a large urban outbreak. Ann Intern Med 1982; 97:680.
17. Wheat LJ, French ML, Wass JL. Sarcoidlike manifestations of histoplasmosis. Arch Intern Med 1989; 149:2421.
18. Picardi JL, Kauffman CA, Schwarz J, Phair JP. Detection of precipitating antibodies to Histoplasma capsulatum
by counterimmunoelectrophoresis. Am Rev Respir Dis 1976; 114:171.
19. Babady NE, Buckwalter SP, Hall L, et al. Detection of Blastomyces dermatitidis and Histoplasma capsulatum

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from culture isolates and clinical specimens by use of real-time PCR. J Clin Microbiol 2011; 49:3204.
20. Bialek R, Cirera AC, Herrmann T, et al. Nested PCR assays for detection of Blastomyces dermatitidis DNA in
paraffin-embedded canine tissue. J Clin Microbiol 2003; 41:205.
21. Tang YW, 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.
22. Goodwin RA Jr, Owens FT, Snell JD, et al. Chronic pulmonary histoplasmosis. Medicine (Baltimore) 1976;
55:413.
23. Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine
(Baltimore) 1988; 67:295.
24. Peikert T, Colby TV, Midthun DE, et al. Fibrosing mediastinitis: clinical presentation, therapeutic outcomes, and
adaptive immune response. Medicine (Baltimore) 2011; 90:412.
25. Davis AM, Pierson RN, Loyd JE. Mediastinal fibrosis. Semin Respir Infect 2001; 16:119.
26. Wheat 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.
27. Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efficacy of liposomal amphotericin B compared with
conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002;
137:105.
28. Dismukes WE, Bradsher RW Jr, Cloud GC, et al. Itraconazole therapy for blastomycosis and histoplasmosis.
NIAID Mycoses Study Group. Am J Med 1992; 93:489.
29. McKinsey DS, Kauffman CA, Pappas PG, et al. Fluconazole therapy for histoplasmosis. The National Institute of
Allergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1996; 23:996.
30. Wheat LJ, Connolly P, Smedema M, et al. Emergence of resistance to fluconazole as a cause of failure during
treatment of histoplasmosis in patients with acquired immunodeficiency disease syndrome. Clin Infect Dis 2001;
33:1910.
31. Restrepo A, Tobn A, Clark B, et al. Salvage treatment of histoplasmosis with posaconazole. J Infect 2007;
54:319.
32. Freifeld AG, Iwen PC, Lesiak BL, et al. Histoplasmosis in solid organ transplant recipients at a large Midwestern
university transplant center. Transpl Infect Dis 2005; 7:109.
33. Freifeld A, Proia L, Andes D, et al. Voriconazole use for endemic fungal infections. Antimicrob Agents Chemother
2009; 53:1648.
34. Putnam, LR, Sutliff, WD, Larkin, JC, et al. Histoplasmosis cooperative study: Chronic pulmonary histoplasmosis
treated with amphotericin B alone and with amphotericin B and triple sulfonamide. Am Rev Respir Dis 1968;
97:96.
35. Hammoud ZT, Rose AS, Hage CA, et al. Surgical management of pulmonary and mediastinal sequelae of
histoplasmosis: a challenging spectrum. Ann Thorac Surg 2009; 88:399.
36. Goodwin RA, Nickell JA, Des Prez RM. Mediastinal fibrosis complicating healed primary histoplasmosis and
tuberculosis. Medicine (Baltimore) 1972; 51:227.
37. Doyle TP, Loyd JE, Robbins IM. Percutaneous pulmonary artery and vein stenting: a novel treatment for
mediastinal fibrosis. Am J Respir Crit Care Med 2001; 164:657.
38. Albers EL, Pugh ME, Hill KD, et al. Percutaneous vascular stent implantation as treatment for central vascular
obstruction due to fibrosing mediastinitis. Circulation 2011; 123:1391.
39. Goodwin RA Jr, Snell JD Jr. The enlarging histoplasmoma. Concept of a tumor-like phenomenon encompassing
the tuberculoma and coccidioidoma. Am Rev Respir Dis 1969; 100:1.
40. Wheat LJ, Stein L, Corya BC, et al. Pericarditis as a manifestation of histoplasmosis during two large urban
outbreaks. Medicine (Baltimore) 1983; 62:110.
41. Picardi JL, Kauffman CA, Schwarz J, et al. Pericarditis caused by Histoplasma capsulatum. Am J Cardiol 1976;
37:82.
42. Rosenthal J, Brandt KD, Wheat LJ, Slama TG. Rheumatologic manifestations of histoplasmosis in the recent
Indianapolis epidemic. Arthritis Rheum 1983; 26:1065.

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Topic 2451 Version 14.0

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GRAPHICS
Pulmonary histoplasmosis

Photomicrograph of an hematoxylin and eosin-stained section of lung


(low power) from a patient with histoplasmosis. Note the granuloma and
inflammation in the surrounding lung tissue.
Courtesy of Harriet Provine.
Graphic 74406 Version 1.0

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Pulmonary histoplasmosis

Silver-stained section of lung tissue (1000x) shows the budding yeast


forms of Histoplasma capsulatum.
Courtesy of Harriet Provine.
Graphic 65482 Version 2.0

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Overview of serology and antigen tests in acute pulmonary


histoplasmosis

Histoplasma capsulatum antigen (Ag) can be detected in patients with acute


pulmonary histoplasmosis and is found more commonly in patients with severe
clinical manifestations. Detection of high titers of complement fixing antibodies to
the yeast or mycelia antigen precedes detection of M or H bands by
immunodiffusion in most patients. However, antibodies rarely appear before the
fourth week of infection and often do not reach maximal titers until the second or
third month of infection.
Courtesy of Joseph Wheat, MD.
Graphic 56766 Version 4.0

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Treatment recommendations for pulmonary manifestations of


histoplasmosis in adults
Syndrome

Recommendation

Acute pulmonary:
moderately

Liposomal AmB 3 mg/kg/day IV or AmB lipid complex 5 mg/kg/day IV or AmB


deoxycholate* 0.7 to 1 mg/kg/day IV for one to two weeks followed by

severe to severe

itraconazole load then 200 mg PO twice daily for a total of 12 weeks


Methylprednisolone, 0.5 to 1 mg/kg/day IV for one to two weeks for respiratory
complications (eg, hypoxemia or respiratory distress)

Acute pulmonary:
mild to moderate

Symptoms <4 weeks: none


Symptoms >4 weeks: itraconazole load then 200 mg once or twice daily for 6 to
12 weeks

Chronic cavitary

Itraconazole load then 200 mg once or twice daily for at least 12 months

pulmonary
Mediastinal
granuloma

Asymptomatic: none
Symptomatic: itraconazole load then 200 mg once or twice daily for 6 to 12
weeks

Mediastinal
fibrosis
Broncholithiasis

Antifungal treatment not recommended


Stenting of obstructed vessels can be useful
None
Bronchoscopic or surgical removal of the broncholith is recommended

Pulmonary nodule

None

AmB: amphotericin B; IV: intravenously; PO: orally.


* The deoxycholate formulation of amphotericin B 0.7 to 1 mg/kg/day is an alternative to a lipid formulation
in patients who are at low risk for nephrotoxicity.
Itraconazole should be given as a loading dose of 200 mg every eight hours for the first three days.
If unable to differentiate mediastinal fibrosis from mediastinal granuloma: Itra 200 mg once or twice daily
for 6 to 12 weeks.

Concentrations of itraconazole in serum should be monitored in patients being treated for chronic

pulmonary histoplasmosis; a random serum concentration >1 mcg/mL should be sought. Drug monitoring is
infrequently needed for patients receiving shorter courses of therapy for acute pulmonary histoplasmosis
and its complications.
Reproduced with permission from: Wheat 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. Copyright 2007 University of Chicago Press.
Graphic 69894 Version 5.0

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Disclosures
Disclosures: Joseph Wheat, MD Employment: MiraVista Diagnostics (Histoplasma antigen testing). Carol A Kauffman, MD Nothing to
disclose. Kieren A Marr, MD Grant/Research/Clinical Trial Support: Pfizer [Antifungals (Voriconazole, anidulafungin)]; Astellas [Transplant
infections (Liposomal amphotericin B, micafungin, isavuconazole)]. Consultant/Advisory Boards: Astellas [Antifungals (Liposomal amphotericin
B, micafungin, isavuconazole)]; Merck [Antifungals (Posaconazole)]; Cidara Therapeutics [Antifungals (Antifungals)]; Chimerix Therapeutics
[Antivirals (Antivirals)]. Patent Holder: MycoMed Technologies [Aspergillosis (Fungal diagnostics)]. Equity Ownership/Stock Options: MycoMed
Technologies [Aspergillosis (Fungal diagnostics)]. Jennifer Mitty, MD, MPH Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy

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