diagnóstico y tratamiento de histoplasmisis pulmonar

Official reprint from UpToDatewww.uptodate.com 2015 UpToDate

Authors

Joseph Wheat, MDCarol A Kauffman, MD

Section Editor

Kieren A Marr, MD

Deputy Editor

Jennifer Mitty, MD, MPH

Diagnosis and treatment of pulmonary histoplasmosis

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:

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]. 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

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

Diagnosis and treatment of pulmonary histoplasmosis http://www.uptodate.com.wdg.biblio.udg.mx:2048/contents/diagnosis-and...

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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 culture-

positive 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:

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.

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


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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:

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].

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


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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:

(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

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


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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 5 to 6 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 10 to

12 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.)

SUMMARY AND RECOMMENDATIONS

th th

th

th

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

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.


8 de 16 17/08/2015 09:30 p.m.

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Hage CA, Davis TE, Fuller D, et al. Diagnosis of histoplasmosis by antigen detection in BAL fluid. Chest 2010;137:623.

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Wheat LJ, Wass J, Norton J, et al. Cavitary histoplasmosis occurring during two large urban outbreaks. Analysisof clinical, epidemiologic, roentgenographic, and laboratory features. Medicine (Baltimore) 1984; 63:201.

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Wheat LJ. Approach to the diagnosis of the endemic mycoses. Clin Chest Med 2009; 30:379.7.

Wheat LJ. Improvements in diagnosis of histoplasmosis. Expert Opin Biol Ther 2006; 6:1207.8.

Swartzentruber S, Rhodes L, Kurkjian K, et al. Diagnosis of acute pulmonary histoplasmosis by antigendetection. Clin Infect Dis 2009; 49:1878.

9.

Lindsley MD, Holland HL, Bragg SL, et al. Production and evaluation of reagents for detection of Histoplasmacapsulatum antigenuria by enzyme immunoassay. Clin Vaccine Immunol 2007; 14:700.

10.

Scheel CM, Samayoa B, Herrera A, et al. Development and evaluation of an enzyme-linked immunosorbentassay to detect Histoplasma capsulatum antigenuria in immunocompromised patients. Clin Vaccine Immunol2009; 16:852.

11.

Cloud JL, Bauman SK, Neary BP, et al. Performance characteristics of a polyclonal enzyme immunoassay for thequantitation of Histoplasma antigen in human urine samples. Am J Clin Pathol 2007; 128:18.

12.

Theel ES, Harring JA, Dababneh AS, et al. Reevaluation of commercial reagents for detection of Histoplasmacapsulatum antigen in urine. J Clin Microbiol 2015; 53:1198.

13.

Theel ES, Jespersen DJ, Harring J, et al. Evaluation of an enzyme immunoassay for detection of Histoplasmacapsulatum antigen from urine specimens. J Clin Microbiol 2013; 51:3555.

14.

Wheat J, Wheat H, Connolly P, et al. Cross-reactivity in Histoplasma capsulatum variety capsulatum antigenassays of urine samples from patients with endemic mycoses. Clin Infect Dis 1997; 24:1169.

15.

Wheat J, French ML, Kohler RB, et al. The diagnostic laboratory tests for histoplasmosis: analysis of experiencein a large urban outbreak. Ann Intern Med 1982; 97:680.

16.

Wheat LJ, French ML, Wass JL. Sarcoidlike manifestations of histoplasmosis. Arch Intern Med 1989; 149:2421.17.

Picardi JL, Kauffman CA, Schwarz J, Phair JP. Detection of precipitating antibodies to Histoplasma capsulatumby counterimmunoelectrophoresis. Am Rev Respir Dis 1976; 114:171.

18.

Babady NE, Buckwalter SP, Hall L, et al. Detection of Blastomyces dermatitidis and Histoplasma capsulatum19.

(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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from culture isolates and clinical specimens by use of real-time PCR. J Clin Microbiol 2011; 49:3204.

Bialek R, Cirera AC, Herrmann T, et al. Nested PCR assays for detection of Blastomyces dermatitidis DNA inparaffin-embedded canine tissue. J Clin Microbiol 2003; 41:205.

20.

Tang YW, Li H, Durkin MM, et al. Urine polymerase chain reaction is not as sensitive as urine antigen for thediagnosis of disseminated histoplasmosis. Diagn Microbiol Infect Dis 2006; 54:283.

21.

Goodwin RA Jr, Owens FT, Snell JD, et al. Chronic pulmonary histoplasmosis. Medicine (Baltimore) 1976;55:413.

22.

Loyd JE, Tillman BF, Atkinson JB, Des Prez RM. Mediastinal fibrosis complicating histoplasmosis. Medicine(Baltimore) 1988; 67:295.

23.

Peikert T, Colby TV, Midthun DE, et al. Fibrosing mediastinitis: clinical presentation, therapeutic outcomes, andadaptive immune response. Medicine (Baltimore) 2011; 90:412.

24.

Davis AM, Pierson RN, Loyd JE. Mediastinal fibrosis. Semin Respir Infect 2001; 16:119.25.

Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients withhistoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45:807.

26.

Johnson PC, Wheat LJ, Cloud GA, et al. Safety and efficacy of liposomal amphotericin B compared withconventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 2002;137:105.

27.

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.

28.

McKinsey DS, Kauffman CA, Pappas PG, et al. Fluconazole therapy for histoplasmosis. The National Institute ofAllergy and Infectious Diseases Mycoses Study Group. Clin Infect Dis 1996; 23:996.

29.

Wheat LJ, Connolly P, Smedema M, et al. Emergence of resistance to fluconazole as a cause of failure duringtreatment of histoplasmosis in patients with acquired immunodeficiency disease syndrome. Clin Infect Dis 2001;33:1910.

30.

Restrepo A, Tobn A, Clark B, et al. Salvage treatment of histoplasmosis with posaconazole. J Infect 2007;54:319.

31.

Freifeld AG, Iwen PC, Lesiak BL, et al. Histoplasmosis in solid organ transplant recipients at a large Midwesternuniversity transplant center. Transpl Infect Dis 2005; 7:109.

32.

Freifeld A, Proia L, Andes D, et al. Voriconazole use for endemic fungal infections. Antimicrob Agents Chemother2009; 53:1648.

33.

Putnam, LR, Sutliff, WD, Larkin, JC, et al. Histoplasmosis cooperative study: Chronic pulmonary histoplasmosistreated with amphotericin B alone and with amphotericin B and triple sulfonamide. Am Rev Respir Dis 1968;97:96.

34.

Hammoud ZT, Rose AS, Hage CA, et al. Surgical management of pulmonary and mediastinal sequelae ofhistoplasmosis: a challenging spectrum. Ann Thorac Surg 2009; 88:399.

35.

Goodwin RA, Nickell JA, Des Prez RM. Mediastinal fibrosis complicating healed primary histoplasmosis andtuberculosis. Medicine (Baltimore) 1972; 51:227.

36.

Doyle TP, Loyd JE, Robbins IM. Percutaneous pulmonary artery and vein stenting: a novel treatment formediastinal fibrosis. Am J Respir Crit Care Med 2001; 164:657.

37.

Albers EL, Pugh ME, Hill KD, et al. Percutaneous vascular stent implantation as treatment for central vascularobstruction due to fibrosing mediastinitis. Circulation 2011; 123:1391.

38.

Goodwin RA Jr, Snell JD Jr. The enlarging histoplasmoma. Concept of a tumor-like phenomenon encompassingthe tuberculoma and coccidioidoma. Am Rev Respir Dis 1969; 100:1.

39.

Wheat LJ, Stein L, Corya BC, et al. Pericarditis as a manifestation of histoplasmosis during two large urbanoutbreaks. Medicine (Baltimore) 1983; 62:110.

40.

Picardi JL, Kauffman CA, Schwarz J, et al. Pericarditis caused by Histoplasma capsulatum. Am J Cardiol 1976;37:82.

41.

Rosenthal J, Brandt KD, Wheat LJ, Slama TG. Rheumatologic manifestations of histoplasmosis in the recentIndianapolis epidemic. Arthritis Rheum 1983; 26:1065.

42.


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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.



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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.



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Treatment recommendations for pulmonary manifestations of

histoplasmosis in adults

Syndrome Recommendation

Acute pulmonary:

moderately

severe to severe

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

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: itraconazole load then 200 mg once or twice daily for 6 to

12 weeks

Chronic cavitary

pulmonary

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

Mediastinal

granuloma

Asymptomatic: none

Symptomatic: itraconazole load then 200 mg once or twice daily for 6 to 12

weeks

Mediastinal

fibrosis

Antifungal treatment not recommended

Stenting of obstructed vessels can be useful

Broncholithiasis 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.



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Disclosures: Joseph Wheat, MD Employment: MiraVista Diagnostics (Histoplasma antigen testing). Carol A Kauffman, MD Nothing todisclose. Kieren A Marr, MD Grant/Research/Clinical Trial Support: Pfizer [Antifungals (Voriconazole, anidulafungin)]; Astellas [Transplantinfections (Liposomal amphotericin B, micafungin, isavuconazole)]. Consultant/Advisory Boards: Astellas [Antifungals (Liposomal amphotericinB, micafungin, isavuconazole)]; Merck [Antifungals (Posaconazole)]; Cidara Therapeutics [Antifungals (Antifungals)]; Chimerix Therapeutics[Antivirals (Antivirals)]. Patent Holder: MycoMed Technologies [Aspergillosis (Fungal diagnostics)]. Equity Ownership/Stock Options: MycoMedTechnologies [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 amulti-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content isrequired of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

Disclosures


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diagnóstico y tratamiento de histoplasmisis pulmonar

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