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Histoplasmosis
Article Last Updated: Jul 2, 2007

AUTHOR AND EDITOR INFORMATION

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Author: James S Hagood, MD, Director, Pediatric Pulmonary Center, Associate
Professor of Pediatrics, Cell Biology and Pathology, Department of Pediatrics,
University of Alabama School of Medicine
James S Hagood is a member of the following medical societies: American
Thoracic Society
Coauthor(s): Asad Ansari, MD, MPH, Pediatric Pulmonary Fellow, Children's
Hospital of Alabama, University of Alabama, Birmingham; Gulnur Com, MD,
Fellow in Pediatric Pulmonology, Department of Pediatrics, Division of Pulmonary
Medicine, University of Alabama School of Medicine
Editors: Glenn J Fennelly, MD, MPH, Director, Division of Pediatric Infectious
Diseases, Jacobi Medical Center; Associate Professor, Department of Pediatrics,
Albert Einstein College of Medicine; Mary L Windle, PharmD, Adjunct Assistant
Professor, University of Nebraska Medical Center College of Pharmacy,
Pharmacy Editor, eMedicine.com, Inc; Larry I Lutwick, MD, Director, Division of
Infectious Diseases, Veterans Affairs New York Harbor Health Care System,
Professor, Department of Internal Medicine, State University of New York at
Downstate; Mary E Cataletto, MD, Associate Director, Division of Pediatric

Pulmonology, Winthrop University Hospital; Associate Professor, Department of

Clinical Pediatrics, State University of New York at Stony Brook; Russell W
Steele, MD, Professor and Vice Chairman, Department of Pediatrics, Head,
Division of Infectious Diseases, Louisiana State University Health Sciences
Center
Author and Editor Disclosure
Synonyms and related keywords: histoplasmosis, Histoplasma capsulatum, H
capsulatum, Histoplasma, fungal pneumonia, tuberculosis, Darling disease,
Darling's disease, fibrosing mediastinitis, pulmonary mycosis, systemic mycosis,
histoplasmin, chronic pulmonary histoplasmosis, CPH, progressive disseminated
histoplasmosis, PDH

INTRODUCTION
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Background
Histoplasmosis is a fungal infection caused by the dimorphic fungus Histoplasma
capsulatum. The fungus grows saprophytically and develops mycelium with
macroconidia and microconidia. The parasitic form is characterized by the
production of yeasts 2-4 m in diameter. Histoplasmosis is endemic in the central
United States and in other parts of the world with warm humid soil and large
populations of migratory birds. It is the most common pulmonary and systemic
mycosis of humans. Clinical manifestations vary from a mild flu-like illness that
often goes unnoticed to rapidly progressive, often fatal, disseminated disease.

The presentation varies depending on the host's immunity and the size of the
inoculum.
The principal challenges to the clinician caring for patients with histoplasmosis
are to recognize the disease, which can mimic a number of processes, and to
rationally use a confusing array of tests for diagnosis and treatment. In 1905,
Samuel Darling described histoplasmosis in a patient working in the Panama
Canal Zone. As early as the 1940s, Amos Christie, MD, and colleagues used the
histoplasmin skin test to demonstrate that numerous patients with abnormal
chest radiographs but negative tuberculin results actually had self-limited
infection with histoplasmosis.

Pathophysiology
Five serotypes of H capsulatum are known, including some avirulent strains.
Histoplasma species have a mycelial form at ambient temperatures. The spores
of H capsulatum (microconidia) become airborne when soil is disturbed (see
Causes).
The initial neutrophil response is ineffective against the yeast form. Macrophages
ingest the yeast, but they continue to proliferate. Specific immunity, which occurs
10-21 days after infection, is needed to kill the organisms. Specific helper T cells
are able to activate macrophages to form the granulomas that are characteristic
of the disease. Natural killer cells mediate extracellular killing, which antibodies
enhance.
Pneumonitis, with a predominant mononuclear infiltrate, peaks 2 weeks after
infection. Granulomas can form in the pulmonary parenchyma and in the hilar
and mediastinal lymph nodes. These lesions can be caseating and may develop
calcification and fibrosis over time. In most infections, fungemia likely occurs at
some point because splenic granulomas have been observed after asymptomatic
infection. In individuals with impaired T cellmediated immunity, other sites of
infection include the bone marrow, liver, adrenal glands, CNS, joint spaces, heart
valves, and blood vessels.
Reports describe infectious complications in almost every tissue. Reactivation of
infection may occur in individuals who become immunosuppressed long after a
primary infection; this reactivation accounts for many of the cases observed in
nonendemic areas. Reinfection can occur in the setting of heavy conidial
burdens, but it is generally mild because of specific immunity.
Recent animal studies have revealed that IL-1, TNF-alpha, and GR 1(+) cells are
important in localizing and controlling Histoplasma infection. YPS3 and cell wall
alpha-(1,3)-glucan of Histoplasma are also associated with virulence.

Frequency

United States
An estimated 50 million individuals have been infected with H capsulatum.
Nationwide, approximately 22% of the population have positive skin-test results
for histoplasmin, though the rate may be as high as 80% in endemic areas in the
central United States, specifically the Ohio and Mississippi River Valleys (see
Image 2). Of the 500,000 individuals who are exposed annually, 50,000-200,000
develop symptoms, and 1500-4000 require hospitalization.
International
Endemic regions for histoplasmosis are found in Central and South America, in
the Caribbean, in Africa, and in Asia. However, microfoci are believed to occur
anywhere soil conditions are appropriate to support the growth of H capsulatum.

Mortality/Morbidity
The overall mortality rate of histoplasmosis is low; most cases spontaneously
resolve. In individuals with immunosuppression, progressive disseminated
disease has a high mortality rate of 7-23%. Without treatment, disseminated
disease is usually fatal. Disseminated infection can localize in any tissue, leading
to various complications. Pericarditis and obstruction of mediastinal structures
are the principal complications in individuals who are immunocompetent.

Race
No racial predilection to infection or to disease presentation is apparent.

Sex
Among adults, histoplasmosis is described more commonly in men than in
women. However, certain clinical manifestations, such as erythema nodosum,
are described most commonly in women. These sex differences in infection and
disease are not observed in children.

Age
Histoplasmosis occurs at any age. Disseminated disease is more likely to occur
in individuals at the extremes of life, unless a person has immunodeficiency. The
incidence of disseminated histoplasmosis in children appears to have decreased
in the last 30 years. The sex-related differences observed in infection and
disease among adults are not observed in children.

CLINICAL
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History
Clinical presentations vary depending on the size of the inoculum, the host's
immune status, and the presence of underlying lung disease. Overt symptoms
occur in 5% of individuals after low-level exposure, but the rate of a clinical
disease exceeds 75% after heavy exposure in healthy hosts. The incubation time
of acute histoplasmosis in previously nonimmune individuals is 9-17 days.
In 80% of patients, symptoms are nonspecific and include fever, chills, myalgias,
nonproductive cough, and chest pain. This acute syndrome can range from mild
(lasting 1-5 d) to severe (lasting 10-21 d); the latter is associated with weight
loss, fatigue, and night sweats. Fatigue may persist for weeks after the acute
symptoms resolve.

Syndromes in immunocompetent hosts

o

Severe acute pulmonary syndrome: After exposure to a large

inoculum, patients may develop severe acute pulmonary syndrome,
which is characterized by a flulike prodrome with severe fever,
chills, fatigue, cough, and chest pain followed by dyspnea and
hypoxemia. This hypoxemia may progress to an adult respiratory
distress syndrome (ARDS)-like illness (see Image 5).

o
o

Histoplasmoma: Histoplasmosis occasionally manifests as a single

pulmonary parenchymal nodule, which is observed as a coin lesion
on chest radiographs. This nodule is often asymptomatic.

Mediastinal obstructive syndromes (granulomatous mediastinitis)

Mediastinal lymph node enlargement occurs in most patients

with histoplasmosis (see Image 1). In 5-10% of patients with
acute pulmonary syndromes, these nodes may be large
enough to obstruct contiguous structures, such as airways,
esophagus, and large blood vessels. Airway obstruction can
lead to a dry or productive cough and dyspnea. In rare
cases, erosion of infected nodes into airway walls can lead
to hemoptysis, air leak syndromes, broncholithiasis, or
lithoptysis.

Esophageal obstruction can cause dysphagia. Airwayesophageal fistulas are reported complications of
mediastinal involvement with histoplasmosis. Obstructed
pulmonary arteries can produce symptoms of mitral valve
obstruction.

Fibrosing mediastinitis is a late complication of mediastinal

granuloma, in which sustained and exaggerated fibrosis
entraps and impinges on mediastinal structures (see Image
6), which may result in venous obstruction. Fibrosing
mediastinitis represents a fibrotic response to a previous
episode of histoplasmosis, and some suggest that certain
individuals are predisposed to excessive fibrotic responses
to Histoplasma antigens. Nonresponses to antifungal
treatment and rare isolations of H capsulatum tissue
samples indicate that ongoing infection is not likely to play
an important role. Presenting symptoms can include cough,
dyspnea, wheezing, hemoptysis, dysphagia, and superior
vena cava (SVC) obstructive syndrome. In a subset of
patients, the process is progressive, leading to death from
cor pulmonale or respiratory failure.

o
o

Pericarditis: Pericarditis usually results from inflammation in

contiguous lymph nodes rather than from fungal infection of the
pericardial space and occurs in as m any as 10% of patients with
symptomatic acute disease.1 Pericarditis with true infection of the
pericardium occasionally occurs in disseminated histoplasmosis.

o
o

Rheumatologic syndrome: A syndrome of arthritis, arthralgias, and

erythema nodosum is observed in as many as 10% of patients with
acute infection. This syndrome is much more common in women
than in men. Joint symptoms can persist for months. In an epidemic
in the Midwestern United States that occurred in the 1980s, 24 of
381 (6.3%) patients with symptomatic histoplasmosis had

rheumatologic symptoms, primarily arthritis or arthralgia. 2 Of these,

46% had erythema nodosum.

Syndromes in hosts with an underlying illness or immunodeficiency

o
Chronic pulmonary histoplasmosis (CPH): CPH most commonly
occurs in adults with underlying lung disease (eg, chronic
obstructive pulmonary disease [COPD]) and represents 10% of
symptomatic cases. Concurrent neoplasia is not uncommon. CPH
is rare in children. The presentation of CPH is similar to that of
pulmonary tuberculosis. Most patients have productive cough,
dyspnea, or chest pain. Systemic symptoms, such as fatigue, fever,
and night sweats, are common. The clinical course of untreated
CPH is progressive, with spread to contiguous lung. Complications,
such as hemoptysis and bronchopleural fistulae, may ensue. Other
infections, such as mycobacterial and other fungal infections (eg,
aspergillosis), can coexist.
o
o

Progressive disseminated histoplasmosis (PDH)

PDH can occur in infants who are immunocompetent but is

most likely to affect patients with underlying disorders of cellmediated immunity. In endemic areas, histoplasmosis
accounts for 5% of opportunistic infections among
individuals with AIDS and may account for 25% in
hyperendemic areas.3 The incidence of histoplasmosis
among individuals with AIDS in the United States has
declined because of widespread use of antiretroviral therapy.
Disseminated histoplasmosis in a patient with HIV can be an
AIDS-defining illness. PDH also occurs in individuals with
Hodgkin disease or lymphoreticular malignancies or in those
receiving immunosuppressive therapy.

In children, the incidence of disseminated histoplasmosis

appears to have decreased in the past 3 decades. The onset
of PDH can be insidious, with low-grade fever, weight loss,
malaise, and oropharyngeal ulcerations. In patients with
severely impaired cellular immunity, the presentation of PDH
may be acute and rapidly progressive. Presenting symptoms
include severe fever, GI symptoms, hepatosplenomegaly,
and pancytopenia. In patients with underlying rheumatic
disease, this may mimic Felty Syndrome.

Multiorgan system failure and coagulopathy can rapidly

ensue. Adrenal involvement is common in PDH (80-90% of
patients), and 15% of patients have overt adrenal
insufficiency.4

Local manifestations of disseminated disease: Histoplasmosis may

include genital ulcers, epididymitis, phimosis, orchitis, cystitis,
cholecystitis, pancreatitis, soft-tissue nodules, nodular myositis,
panniculitis, carpal tunnel syndrome, osteomyelitis, arthritis, and
hypercalcemia. The occurrence of ocular histoplasmosis is
controversial because this clinical entity is described in patients
who reside exclusively in areas where histoplasmosis in not
endemic.

o
o

CNS histoplasmosis: Meningitis is a complication in 10% of patients

with disseminated disease but occasionally occurs in patients who
are immunocompetent.1, 5 Symptoms are usually indolent and
chronic; examples include fever, headache, and changes in mental
status. Seizures and focal neurologic deficits can occur. Localized
lesions in the brain occur in one third of patients with CNS
involvement, and isolated spinal cord lesions have been reported.

o
o

Adrenal disease may occur as a manifestation of relapsing

histoplasmosis several years after the initial episode. Concurrent
CNS involvement is common in patients with adrenal involvement.
Histoplasmosis should be excluded in all patients with adrenal
insufficiency or adrenal masses, and CT scanning to examine the
adrenal glands should be considered in patients with disseminated
histoplasmosis.

o
o

Endocarditis is reported in 4% of patients with disseminated

histoplasmosis, and mostly presents with embolic episodes. 1

Physical

Syndromes in immunocompetent hosts

o
o

Severe acute pulmonary syndrome: Physical findings are similar to

those of diffuse pneumonitis and include increased work of
breathing, nasal flaring, accessory muscle use, and diffuse fine
crackles. Pleural involvement can present with pleural friction rub or
with diminished breath sounds and dullness to percussion.
Mediastinal obstructive syndromes: Obstruction of central airways
can produce inspiratory and expiratory wheezes, which may be
monophonic and localized. Findings in SVC syndrome include
facial swelling, distension of the veins of the neck and upper chest
wall, conjunctival injection, and loss of venous pulsations.
Pulmonary venous occlusion produces findings consistent with
mitral valve stenosis, including a low-pitched diastolic apical
murmur.

o
o

o
o

Pericarditis: Physical findings include chest/abdominal pain,

pericardial friction rub, and fever. Signs of hemodynamic
compromise can be observed in 40% of patients. 1
Rheumatologic syndrome: In a subset of patients, symmetric
polyarticular arthritis and erythema nodosum may be seen.

Syndromes in hosts with an underlying illness or immunodeficiency

o

o
o

CPH: Crackles, wheezes, and diminished breath sounds may be

heard. Other physical findings are similar to those observed in
chronic lung disease. Examples are cyanosis and digital clubbing.
PDH: Patients usually have respiratory distress, inanition, cachexia,
pallor, and hepatosplenomegaly. Subcutaneous nodules may be
present, as may signs of localized infection in almost any tissue or
organ.

Causes

The spores of H capsulatum (microconidia) become airborne when soil is

disturbed.
High numbers of spores are present in microfoci of soil heavily
contaminated with bird or bat droppings, such areas as under bird roosts
or in caves (see Image 4).
Urban and suburban outbreaks in endemic areas are often associated
with large-scale construction or cleaning projects in which soil is disturbed.
The microconidia (1-5 m in diameter) are easily inhaled and deposited in
distal air spaces.
At body temperature, proliferation of the yeast (infective) form of the
organism occurs within 3-5 days.
Histoplasmosis can occur in almost all mammals. Although the fungus
thrives in bird droppings, birds are not infected. However, bats can be
infected with H capsulatum. Direct animal-to-human or human-to-human
transmissions are not thought to occur.

DIFFERENTIALS
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Blastomycosis
Coccidioidomycosis
Pneumonia
Respiratory Distress Syndrome
Sarcoidosis
Tuberculosis

Other Problems to be Considered

Lung abscess
Lung cancer
Lymphoma

WORKUP
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Lab Studies

General considerations

The laboratory diagnoses of fungal disease and histoplasmosis are

particularly challenging because of the nonspecific clinical findings,
the difficulty of culturing organisms, and the confusing array of tests
available. MiraVista Diagnostics has established a Web site to
assist clinicians.

o
o

General laboratory findings in disseminated disease include

pancytopenia, elevated liver enzyme levels, hyperbilirubinemia, and
elevated serum lactate dehydrogenase (LDH) levels.

o
o

Silver stain of tissue sections or Wright stain of smears of

peripheral blood or bone marrow aspirates are useful for
diagnosing acute disseminated infection or severe pulmonary
infection.

Culturing

The criterion standard of diagnosis is culture of the fungus from

clinical specimens.

o
o

H capsulatum can be recovered from sputum, bronchoalveolar

lavage (BAL), skin lesions, blood, or bone marrow on routine fungal
cultures, but the organism grows slowly, and plates must be kept as
long as 12 weeks. A DNA probe for H capsulatum permits rapid
identification.

o
o

Blood culture by using the lysis-centrifugation system is somewhat

more rapid and increases sensitivity.

o
o

Cultures are positive in as many as 85% of patients with PDH or

CPH, but they can be falsely negative in about 20% of
disseminated cases.

o
o

The combination of blood and bone marrow cultures increases the

likelihood of positive cultures.

o
o

Bronchoscopy is an important diagnostic tool, especially for PDH,

with a diagnostic yield of 60% in patients from endemic areas with
pulmonary infiltrates and 88% for chronic cavitary histoplasmosis.

o
o

Use of several specimens may increase the yield.

Skin testing

Histoplasmin skin testing is not recommended for diagnostic

purposes because of the high rate of positive reactions in endemic
areas, because of the variable duration of responses to the skin
test, and because of skin testing can affect the results of
subsequent serologic tests.

o
o

Skin testing has been useful as an epidemiologic tool.

Serologic testing

A number of tests have been developed to detect H capsulatum

antigen or host antibodies to infection. Tests to detect host
antibodies are those more commonly used in the clinical setting.
However, test results for antibodies can be falsely negative in
patients with disseminated disease because of underlying
immunosuppression. On the other hand, patients with disseminated
disease have a high fungal burden that enables rapid diagnosis by
means of antigen detection. Because of the low fungal burden in
patients with mild manifestations, the yield of antigen detection is
low.

o
o

Antibody levels peak 6 weeks after exposure and decline over 2-5
years. Elevated antihistoplasmal antibody levels might result from a
previous infection or after other types of fungal infections.

Antibody testing

The standard serologic tests for histoplasmosis are the

immunodiffusion (ID) test and the complement fixation (CF) test.

o
o

Histoplasmin, a filtrate of mycelial cultures, is the antigen used in

the ID test. Two possible precipitin bands are observed: The H
band reflects antibodies formed during active infection and
becomes undetectable within 6 months. The M band is present in
acute and chronic acute and chronic infection and remains elevated
for years. This test is less sensitive than CF and should not be used
for screening. M precipitins can be detected in 50-75% of patients
with acute histoplasmosis and in almost 80-100% of patients with
chronic pulmonary infections.

The CF test uses both mycelial and yeast phase antigens. An

antibody to a yeast-phase CF titer of more than 1:32 is consistent
with active infection in an endemic area, though an acute titer of
more than 1:8 suggests infection, especially in nonendemic areas.
CF has higher sensitivity than ID. In acute pulmonary
histoplasmosis, the CF result is positive in 90% of patients,
whereas the sensitivity of ID is as much as 75%.

o
o

A 4-fold rise in titer between acute and convalescent paired sera is

diagnostic. Antibodies may clear within months after a brief
exposure but might persist for years after a prolonged exposure.

o
o

Although CF and ID both are fairly specific, some cross-reactivity

with other mycoses occurs.

o
o

Radioimmunoassay (RIA) and subsequent enzyme immunoassay

(EIA) have been reported to be more sensitive than CF; however,
higher background seropositivity in endemic areas and recent
studies questioning the sensitivity of these assays compared with
CF limit their usefulness.6

o
o

Antibody responses can also be measured with enzyme

immunoassay or Western blot assay. Although antibodies can be
detected faster with these methods than with standard tests, these
methods are difficult to standardize and their results are hard to
quantitate and interpret.

Antigen testing

Detection of polysaccharide antigen in serum, urine, or BAL of

patients with disseminated and acute pulmonary histoplasmosis is
a rapid and specific diagnostic method. Urine specimens have high
sensitivity, as much as 90% in immunocompetent patients with
disseminated or acute pulmonary disease. BAL fluid antigen levels
can be higher than those in blood or urine, and matched BAL,
urine, and serum specimens have the highest yield.

o
o

The recommended approach is first to perform antigen testing with

blood and urine from a patient with suspected histoplasmosis.
Then, the focus in testing depends on the symptoms. For example,
in patients with respiratory symptoms, obtain BAL samples; in those
with CNS symptoms, obtain CSF.

o
o
o

Cross-reactivity with other endemic mycoses occurs.

If initial results are positive, the antigen test can be used to monitor
the treatment response. Antigen levels decrease with treatment,
eventually reaching undetectable levels in patients who are cured
or in patients undergoing chronic maintenance treatment.
Persistent antigenemia or antigenuria indicates an ongoing
infection and supports the continuation of antifungal therapy.
Antigen levels rise during relapse, enabling detection in patients
whose antifungal treatment has been discontinued.

o
o

Recently, Histoplasma antigen detection by means of enzymelinked immunosorbent assay (ELISA) has become available for
different specimens, including serum, urine, BAL, and CSF
samples. The sensitivity of this test is reported to be as high as
92% in urine specimens and 82% in serum specimens from
patients with disseminated histoplasmosis. 1, 7 Although the
sensitivity is low in self-limited and CPH, the specificity is as much
as 98%.

Molecular diagnostic testing

Preliminary data suggest that polymerase chain reaction (PCR)

might improve the accuracy of identifying H capsulatum in tissue
specimens.8, 9 DNA probes are also commercially available and are
used for definitive identification of positive cultures. DNA probes are
also commercially available and are used for confirmation of
positive cultures.

o
o

A retrospective review of pediatric patients with cancer at St Jude

Children's Research Hospital demonstrated that the most rapid and
specific tests for histoplasmosis were histopathologic examination
of lung biopsy specimens in patients with localized pulmonary
infection and Histoplasma-specific antigen detection in the urine of
patients with disseminated histoplasmosis. 10

Imaging Studies

Syndromes in immunocompetent hosts

o
o

Acute pulmonary syndrome: Plain chest radiography may

demonstrate enlarged mediastinal lymph nodes and small
reticulonodular infiltrates, with or without small bilateral pleural
effusions. More severe acute pulmonary syndromes have more
prominent diffuse infiltrates (see Image 5).
Mediastinal obstructive syndromes: Enlarged mediastinal lymph
nodes or granulomas, with or without calcification, are often

observed on plain chest radiographs (see Image 1). In fibrosing

mediastinitis, roentgenographic findings can be subtle and include
superior mediastinal widening or carinal splaying (see Image 6). CT
demonstrates the extent of mediastinal involvement better than
chest radiography. Other studies, such as esophagography,
vascular contrast studies, and ventilation-perfusion scanning, can
be useful to determine the extent of obstructive involvement of
mediastinal structures.
o
o

Pericarditis: Echocardiography demonstrates pericardial fluid, but

findings are nonspecific.

Syndromes in hosts with an underlying illness or immunodeficiency

o
o

CPH: Radiographic manifestations of CPH include apical

fibronodular opacities, cavitary lesions, and pleural thickening. CT
scanning may be helpful in defining lesions in the context of
underlying lung disease.
CNS histoplasmosis: Localized enhancing lesions, single or
multiple, can be observed on CT scanning or MRI.

Other Tests

Pulmonary function testing may demonstrate fixed or variable airway

obstructive patterns in mediastinal obstructive syndromes.
Acute pulmonary disease is most likely to demonstrate a restrictive
pattern.
A recent small study found that testing of fecal mucus for Histoplasma was
helpful in diagnosing disseminated histoplasmosis in children.

Procedures

Pericardiocentesis: Pericarditis may occur in 10% of patients who are

symptomatic. Pericardiocentesis yields bloody sterile pericardial fluid.
Bronchoscopy: In acute severe pulmonary syndromes, bronchoscopy with
bronchial washing may be indicated to obtain diagnostic material. In
chronic pulmonary forms, bronchoscopy with bronchial brushing or
transbronchial biopsy may be indicated to obtain samples and to rule out
malignancy. Bronchoscopy also may be useful in hemoptysis and
broncholithiasis.

Biopsy: Biopsy of the affected tissues can be performed during open

procedures or thoracoscopy.
Lumbar puncture: In CNS histoplasmosis, the results of lumbar puncture
demonstrate lymphocytic pleocytosis, with elevated protein and normal or
low glucose values.

Histologic Findings
Pulmonary histoplasmosis has a predominantly mononuclear infiltrate. Multiple
granulomas, with multinucleated giant cells, are characteristic findings. Large
granulomas are often caseating. The periphery of granulomas may show fibrosis,
and calcification of central areas may be present. On hematoxylin and eosin
staining, the yeast form of H capsulatum has a false capsule (see Image 3).
Special stains, such as Gomori methenamine silver (GMS) or periodic acid-Schiff
(PAS), may reveal budding yeast, but the organisms can be mistaken for
Pneumocystis carinii and other fungal organisms. In chronic pulmonary forms, in
addition to underlying lung disease, vascular involvement, tissue necrosis, and
scarring are present. Extensive fibrosis with collagen deposition is observed in
fibrosing mediastinitis.

TREATMENT
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Medical Care

Most acute forms of histoplasmosis in immunocompetent hosts resolve without

specific treatment. Systemic antifungal treatment is indicated for severe acute
pulmonary histoplasmosis, CPH, PDH, and any manifestation in an
immunocompromised patient. Specific therapy recommendations vary with the
presenting syndrome.

Syndromes in immunocompetent hosts

o
o

o
o

o
o

Localized disease: Antifungal therapy is unnecessary in patients

with localized disease. However, oral itraconazole is recommended
for 6-12 weeks in patients whose symptoms have not improved
after 3-4 weeks of observation.
Severe acute pulmonary syndrome: Antifungal therapy
(amphotericin B) is indicated for patients presenting with clinically
significant dyspnea or hypoxemia. After discharge from the hospital,
itraconazole should be used to complete a 12-week course of
antifungal therapy. Patients with relatively mild manifestations can
be treated with only itraconazole, and treatment should be
continued for 3 months. Corticosteroids have also been used for
short-term therapy (tapered over 2 wk); however, these agents
always should be used with caution in fungal infections because of
the risk of impaired cell-mediated immunity with prolonged use.
Mediastinal obstructive syndromes: For patients with clinically
significant, symptomatic obstructive symptoms, antifungal treatment
should be started. Reports describe successful treatment with oral
(eg, itraconazole, ketoconazole) and systemic (amphotericin B)
antifungal agents. Surgical resection should be considered for lifethreatening obstruction or if a patient's condition fails to improve
after 4-6 weeks of antifungal treatment. Surgical interventions do
not prevent progression to fibrosing mediastinitis. Although reports
mention successful surgical management of fibrosing mediastinitis,
the surgical mortality rate is high, and surgeons inexperienced in
managing this disorder should not attempt such interventions.
Medical management with antifungal agents should be attempted
first unless the obstruction is life threatening.
Pericarditis: Anti-inflammatory treatment with nonsteroidal antiinflammatory drugs (NSAIDs) or corticosteroids is the mainstay of
management. Progression to constrictive pericarditis is described
but rare.
Rheumatologic syndrome: Rheumatologic syndrome often resolves
without treatment or with a brief course of NSAIDs.

Syndromes in hosts with an underlying illness or immunodeficiency

o
o

CPH: Without antifungal treatment, CPH is progressive, causing

loss of pulmonary function in most patients and death in up to half.
Amphotericin B has been used most successfully and is effective in
59-100% of cases, but most patients can be treated with
itraconazole or ketoconazole for at least 3 months.1 Relapse rates
are 10-15% with the last 2 agents; fluconazole is less effective. The
preferred treatment is amphotericin B followed by itraconazole for
12-24 months.
PDH

o
o

Amphotericin B substantially reduces the mortality rate of

PDH. A cumulative dosage of at least 35 mg/kg should be
administered to prevent relapse. Liposomal preparations
may be substituted to reduce toxicity but may have poor
renal penetration.
Many patients have been treated successfully with a change
to oral agents after their symptoms initially improve with
amphotericin B. Itraconazole is the preferred oral agent, with
a 6- to 18-month course of treatment. Patients who cannot
tolerate itraconazole should use fluconazole. After an initial
12-week intensive phase with amphotericin B to induce a
remission, patients with AIDS require chronic life-long
maintenance therapy to prevent relapse. Amphotericin B
once or twice a week is effective but inconvenient and not
well tolerated.
Azoles are highly effective in most cases, but relapse may
occur. Treatment with fluconazole is discouraged because of
its reduced efficacy as long-term maintenance therapy for
histoplasmosis. Echinocandins should not be used.

Local manifestations of disseminated disease: Endocarditis is very

difficult to treat and may require resection of the affected valve and
systemic antifungal treatment.

Surgical Care
Surgical consultation is indicated for patients with infections complicated by
fistulas, hemoptysis, or broncholithiasis. The surgical management of mediastinal
obstructive syndromes is somewhat controversial because they may improve
with observation or medical therapy. Severe obstruction of the airways or large
blood vessels may be life threatening, and immediate intervention may be
required.

In general, unroofing and debridement of large granulomas is preferable to

excision. Fibrosing mediastinitis is especially difficult to manage because normal
structures are encased in collagenous connective tissue. Surgeons in endemic
areas often are well versed in the management of these surgically challenging
problems.

Consultations
Infectious disease specialists can assist in the differential diagnosis, in planning
appropriate workup, and in choosing therapeutic regimens, particularly for
immunocompromised patients.

Activity
Bed rest has been recommended for systemic syndromes.

MEDICATION
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Always consult the latest information regarding the drugs of choice (DOCs), the
dosages, and the routes of administration. Consultation with infectious diseases
specialists can be helpful in choosing appropriate therapy.
Drug Category: Antifungal agents

Systemic antifungal treatment is indicated for severe acute pulmonary

histoplasmosis, CPH, PDH, and any manifestation in an immunocompromised
patient (see Treatment).
Amphotericin B is the mainstay of therapy for most systemic fungal infections. It
is highly effective, but it has potential adverse effects. New lipid formulations of
amphotericin B reduce renal toxicity; however, they are expensive and their
improvements in efficacy are not proven. A double-blind randomized trial
performed to compare liposomal amphotericin B (L-AMB) with the standard
formulation (AmB) in patients with AIDS showed that L-AMB was at least as
effective as AmB, with marked reduction in renal toxicity.11
Echinocandins (eg, caspofungin) should not be used.
Drug Name

Amphotericin B (Amphocin, Fungizone)

Description

Produced by strain of Streptomyces

nodosus. Fungistatic or fungicidal. Binds
to sterols (eg, ergosterol) in fungal cell
membrane, causing intracellular
components to leak, with subsequent
fungal cell death. DOC for severe or
disseminated histoplasmosis.

Adult Dose

1 mg IV test dose, then increase by 0.5-1

mg/kg/d; not to exceed 1.5 mg/kg/d;
infuse over 2-6 h

Pediatric Dose

0.1 mg/kg IV test dose; if tolerated,

administer additional 0.4 mg/kg the same
day; increase by 0.5-1 mg/kg/d; not to
exceed 1.5 mg/kg/d

Contraindications Documented hypersensitivity

Interactions

Antineoplastic agents may enhance

potential for renal toxicity,
bronchospasm, and hypotension;
corticosteroids, digitalis, and thiazides
may potentiate hypokalemia;
cyclosporine increases risk of renal
toxicity

Pregnancy

B - Usually safe but benefits must

outweigh the risks.

Precautions

Caution in renal impairment; monitor

BUN and creatinine qod as dosage
increases; patients with renal disease or
intolerance of standard preparations may
best tolerate lipid or liposomal forms;

may offer theoretic advantage of high

tissue levels; being compared with
standard preparations to treat
histoplasmosis
Monitor renal function, serum electrolyte
(eg, magnesium, potassium levels), liver
function, CBCs, and hemoglobin
concentrations; resume therapy at lowest
level (eg, 0.25 mg/kg) when interrupted
for >7 d
Hypoxemia, acute dyspnea, and
interstitial infiltrates may occur in
neutropenic patients receiving leukocyte
transfusions (separate amphotericin
infusion from leukocyte transfusion);
fever and chills not uncommon after first
few administrations; rare acute reactions
include hypotension, bronchospasm,
arrhythmias, and shock
Drug Category: Antifungal agents, azoles
The azole antifungal agents are divided into 2 groups: imidazoles and triazoles.
The imidazoles are an older group and include miconazole, ketoconazole, and
clotrimazole. The triazoles consist of fluconazole; itraconazole; and the new
second-generation azoles ravuconazole (investigational in the United States),
voriconazole, and posaconazole.
Itraconazole is more effective than ketoconazole or fluconazole for treatment of
histoplasmosis. It is also effective for long-term suppression of histoplasmosis in
patients with AIDS.
Voriconazole and posaconazole may be useful in patients who are intolerant of or
who fail treatment with AmB or itraconazole. In vitro studies with voriconazole
and posaconazole have shown the activity of these agents against H
capsulatum, Blastomyces dermatitidis, and Coccidioides immitis. Data from a few
animal studies have verified their efficacy in vivo. 12, 13
Posaconazole is reported to be effective for histoplasmosis in a small number of
patients. In a case series, 6 of 7 patients were successfully treated with
posaconazole.14 Four of these 6 patients had disseminated infection, and, in all,
other therapy failed or was intolerable.
Phase 3 clinical trials for the treatment of invasive fungal infections have been
completed, and the US Food and Drug Administration recently approved

posaconazole for the prophylaxis of invasive Aspergillus and Candida infections

in high-risk, severely immunocompromised patients aged 13 years or older.
Drug Name

Itraconazole (Sporanox)

Description

Synthetic triazole antifungal agent. Can

be used in CPH, but relapse rate higher
than with amphotericin B.

Adult Dose

200 mg PO qd, may increase by

increments of 100 mg/d; not to exceed
400 mg/d divided bid

Pediatric Dose

Contraindications

Not established, limited data suggest 3-5

mg/kg/d PO
Disseminated histoplasmosis: 6-8
mg/kg/d PO
Prophylaxis in children with HIV infection:
2-5 mg/kg PO q12-48h
Documented hypersensitivity; CNS
histoplasmosis

Interactions

Inhibits cytochrome P450 (CYP) 3A4;

antacids may reduce absorption; edema
may occur with coadministration of
calcium channel blockers (eg,
amlodipine, nifedipine); hypoglycemia
may occur with sulfonylureas; may
increase tacrolimus and cyclosporine
plasma concentrations when high doses
used; rhabdomyolysis may occur with
coadministration of beta-hydroxy-betamethylglutarylcoenzyme A (HMG-CoA)
reductase inhibitors (lovastatin or
simvastatin); coadministration with
cisapride can cause cardiac rhythm
abnormalities and death
May increase digoxin levels;
coadministration may increase plasma
levels of midazolam and triazolam;
phenytoin and rifampin may reduce
levels (may alter phenytoin metabolism)

Pregnancy

C - Safety for use during pregnancy has

not been established.

Precautions

Caution in hepatic impairment (monitor

liver function); concomitant use of CYP
substrates with decreased clearance (eg,
cisapride) may result in toxicity

Drug Name

Ketoconazole (Nizoral)

Description

Synthetic imidazole antifungal agent.

Can be used for CPH, but relapse rate
higher than that of amphotericin B.

Adult Dose

200-400 mg PO qd/bid

Pediatric Dose

3.3-6.6 mg/kg PO qd

Documented hypersensitivity;
concomitant use with CYP substrates
Contraindications
with decreased clearance (eg, cisapride)
may result in toxicity

Interactions

Potent CYP3A inhibitor; isoniazid may

decrease bioavailability; coadministration
of rifampin decreases effects of both;
may increase effect of anticoagulants;
may increase toxicity of cyclosporine
(adjust dosage) and corticosteroids and
other CYP3A substrates; may decrease
theophylline levels; administer antacids,
anticholinergics, or H2 blockers at least 2
h after ketoconazole dose

Pregnancy

C - Safety for use during pregnancy has

not been established.

Precautions

Efficacy against H capsulatum less well

established than with amphotericin B and
itraconazole (use only as alternative to
these agents); hepatotoxicity may occur

Drug Name

Fluconazole (Diflucan)

Description

Synthetic triazole antifungal with low

plasma protein binding. CNS penetration
better than that of imidazoles.

Adult Dose

400 mg/d PO/IV for CNS histoplasmosis

or for prophylaxis in immunosuppressed
patients

Pediatric Dose

12 mg/kg/d IV/PO; not to exceed 600

mg/d

Contraindications Documented hypersensitivity

Interactions

Inhibits CYP3A4; levels may increase

with hydrochlorothiazide; long-term
coadministration of rifampin may
decrease levels; coadministration may
decrease phenytoin clearance; may

increase theophylline, tolbutamide,

glyburide, and glipizide concentrations;
coadministration may increase effects of
anticoagulants; may increase
cyclosporine concentrations when
administered concurrently
Pregnancy

C - Safety for use during pregnancy has

not been established.

Precautions

Decreased activity against H capsulatum

versus other azoles; caution in impaired
renal function; periodically monitor liver
and renal function

Drug Name

Posaconazole (Noxafil)

Description

Triazole antifungal agent. Blocks

ergosterol synthesis by inhibiting
lanosterol 14-alpha-demethylase and the
accumulation of sterol precursors. Action
disrupts cell membrane. Available as PO
susp 200 mg/5 mL. Indicated for
prophylaxis of invasive Aspergillus and
Candida infections in patients at high risk
because of severe immunosuppression.

Adult Dose

200 mg (5 mL) PO tid with food or liquid

nutritional supplement to enhance
absorption

Pediatric Dose

<13 years: Not established

>13 years: Administer as in adults

Documented hypersensitivity;
coadministration with ergot alkaloids;
coadministration with CYP3A4 substrates
Contraindications
(eg, terfenadine, astemizole, cisapride,
pimozide, halofantrine, quinidine) likely to
cause serious toxicities
Interactions

Metabolized by means of uridine

diphosphate (UDP) glucuronidation; Pglycoprotein (P-gp) efflux substrate;
CYP3A4 inhibitor
UDP glucuronidation inducers (eg,
rifabutin, phenytoin) and drugs that
increase gastric pH (eg, cimetidine)
decrease serum levels (avoid
concomitant use unless benefit
outweighs risk)

Inhibits CYP3A4 and may elevate serum

levels of cyclosporine, tacrolimus,
sirolimus, rifabutin, midazolam,
phenytoin, calcium channel blockers (eg,
nifedipine, bepridil), HMG-CoA reductase
inhibitors (eg, lovastatin, pravastatin),
ergot alkaloids, terfenadine, astemizole,
cisapride, pimozide, halofantrine,
quinidine, or vinca alkaloids (eg,
vincristine, vinblastine)
Pregnancy

Precautions

C - Safety for use during pregnancy has

not been established.
Common adverse effects include
nausea, vomiting, diarrhea, rash,
hypokalemia, thrombocytopenia, and
elevated liver enzyme levels; closely
monitor patients with severe diarrhea or
vomiting for breakthrough fungal
infections; rare adverse events include
arrhythmias caused by QTc prolongation,
bilirubinemia, or liver dysfunction; caution
in preexisting cardiac risk factors (eg,
history of arrhythmia, hypokalemia,
hypomagnesemia); food improves
absorption and provides optimal serum
concentration; shake well before use;
administer with measuring spoon in
package; avoid if breastfeeding

Drug Category: NSAIDs

NSAIDs have analgesic, anti-inflammatory, and antipyretic activities. Their
mechanism of action is not known, but they may inhibit cyclooxygenase activity
and prostaglandin synthesis. Other mechanisms may include inhibition of
leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity,
neutrophil aggregation, and various cell-membrane functions. A brief course of
NSAIDs may be required for patients who develop rheumatologic symptoms.
Drug Name

Naproxen (Aleve, Naprosyn)

Description

For relief of mild to moderate pain;

inhibits inflammatory reactions and pain
by decreasing activity of cyclooxygenase,
which is responsible for prostaglandin
synthesis.

Adult Dose

250-500 mg PO bid; may increase to 1.5

g/d for limited periods

Pediatric Dose

<2 years: Not established

>2 years: 2.5 mg/kg PO q12h; may
increase dose, not to exceed 10 mg/kg/d

Documented hypersensitivity; peptic

Contraindications ulcer disease; recent GI bleeding or
perforation; renal insufficiency

Interactions

Coadministration with aspirin increases

risk of serious NSAID-related adverse
effects; probenecid may increase
concentrations and, possibly, toxicity;
may decrease effect of hydralazine,
captopril, and beta-blockers; may
decrease diuretic effects of furosemide
and thiazides; may increase prothrombin
time (PT) with anticoagulants (instruct
patients to watch for signs of bleeding);
may increase risk of methotrexate
toxicity; may increase phenytoin levels
when administered concurrently

Pregnancy

B - Usually safe but benefits must

outweigh the risks.

Precautions

Category D in third trimester of

pregnancy; acute renal insufficiency,
interstitial nephritis, hyperkalemia,
hyponatremia, and renal papillary
necrosis may occur; patients with
preexisting renal disease or
compromised renal perfusion at risk for
acute renal failure; leukopenia occurs
rarely, is transient, and usually resolves
during therapy; persistent leukopenia,
granulocytopenia, or thrombocytopenia
warrants further evaluation and
discontinuation may be required

Drug Name

Ibuprofen (Motrin, Advil, Ibuprin)

Description

Inhibits inflammatory reactions and pain

by decreasing prostaglandin synthesis.

Adult Dose

400 mg PO q4-6h, 600 mg q6h, or 800

mg q8h while symptoms persist; not to
exceed 3.2 g/d

Pediatric Dose

20-70 mg/kg/d PO divided tid/qid; start at

lower end of dosing range and titrate; not

to exceed 2.4 g/d
Documented hypersensitivity; peptic
ulcer disease, recent GI bleeding or
Contraindications
perforation, renal insufficiency, or high
risk of bleeding

Interactions

Coadministration with aspirin increases

risk of serious NSAID-related adverse
effects; probenecid may increase
concentrations and, possibly, toxicity;
may decrease effect of hydralazine,
captopril, and beta-blockers; may
decrease diuretic effects of furosemide
and thiazides; may increase PT with
anticoagulants (instruct patients to watch
for signs of bleeding); may increase risk
of methotrexate toxicity; may increase
phenytoin levels when administered
concurrently

Pregnancy

B - Usually safe but benefits must

outweigh the risks.

Precautions

Category D in third trimester of

pregnancy; caution in congestive heart
failure, hypertension, and decreased
renal and hepatic function; caution in
coagulation abnormalities or during
anticoagulant therapy

FOLLOW-UP
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Prognosis

Most cases of histoplasmosis spontaneously resolve and do not recur.

Reinfection is possible, as is reactivation in individuals from endemic
areas who become immunosuppressed.
The mortality rate of disseminated disease even with appropriate
treatment is high (7-23%); without treatment it is as high as 80%.
Poor clinical response or relapse may indicate insufficient total dose of
antifungal agent, unrecognized immunosuppression, or occult localized
infection, such as endocarditis or meningitis.
Relapse occurs in 10-20% of patients with disseminated infection and in
as many as 80% of those with AIDS.

Patient Education

Prevention of histoplasmosis can be difficult because the source of

organisms cannot always be determined, although reports of
decontamination of environmental sources have been reported.
Immunocompromised individuals should be counseled to avoid situations
in which the likelihood of exposure is high, such as spelunking or outdoor
construction projects in endemic areas where significant disturbance of
soil occurs.
For excellent patient education resources, visit eMedicine's Procedures
Center. Also, see eMedicine's patient education article Bronchoscopy.

MISCELLANEOUS
Section 9 of 11
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Treatment
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Medical/Legal Pitfalls

Histoplasmosis has varied and often subtle presentations and has been
misdiagnosed as many other entities.
Treating patients who have moved from an endemic area to a nonendemic
area and subsequently develop impaired immunity can be challenging for
clinicians not familiar with the manifestations of histoplasmosis.
Misdiagnosis as sarcoidosis can be problematic if the patient is treated
with systemic corticosteroids or TNF-alpha blocking agents, which may
cause progression or dissemination. Fatalities have been described.

MULTIMEDIA
Section 10 of 11
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Media file 1: Hilar lymphadenopathy in an 11-year-old child.

View Full Size Image

Media type: X-RAY

Media file 2: Map demonstrates the distribution of histoplasmin skin-test
positivity by region. Used with permission from the American Thoracic
Society.
View Full Size Image

Media type: Graph

Media file 3: Hematoxylin and eosin stain of infected lung tissue. Histoplasma
organisms appear to have a false capsule.
View Full Size Image

Media type: Photo

Media file 4: Starling roost in Alabama.
View Full Size Image

Media type: Photo

Media file 5: Acute pulmonary syndrome in a 16-year-old female adolescent.
View Full Size Image

Media type: X-RAY

Media file 6: Fibrosing mediastinitis with mediastinal widening and tracheal
deviation.
View Full Size Image

Media type: X-RAY

REFERENCES
Section 11 of 11
Authors and Editors
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Clinical
Differentials
Workup
Treatment
Medication
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Multimedia
References

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