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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
JamesSHagoodis 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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BackgroundHistoplasmosis 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.
PathophysiologyFive 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.
Recentanimal 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.
FrequencyUnited 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/MorbidityThe 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.
RaceNo racial predilection to infection or to disease
presentation is apparent.
SexAmong 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.
AgeHistoplasmosis 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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HistoryClinical 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
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).
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 enlargementoccurs 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. Airway-esophageal
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.
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.
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
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.
Progressive disseminated histoplasmosis (PDH)
PDH can occur in infants who are immunocompetent but is most
likely to affect patients with underlying disorders of
cell-mediated 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.
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.
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.
Endocarditis is reported in 4% of patients with disseminated
histoplasmosis, and mostly presents with embolic episodes.1Physical
Syndromes in immunocompetent hosts
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.
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
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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BlastomycosisCoccidioidomycosisPneumoniaRespiratory Distress
SyndromeSarcoidosisTuberculosisOther Problems to be Considered
Lung abscess Lung cancerLymphoma
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.
General laboratory findings in disseminated disease include
pancytopenia, elevated liver enzyme levels, hyperbilirubinemia, and
elevated serum lactate dehydrogenase (LDH) levels.
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.
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.
Blood culture by using the lysis-centrifugation system is
somewhat more rapid and increases sensitivity.
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.
The combination of blood and bone marrow cultures increases the
likelihood of positive cultures.
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.
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.
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.
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.
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%.
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.
Although CF and ID both are fairly specific, some
cross-reactivity with other mycoses occurs.
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
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.
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.
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.
Recently, Histoplasma antigen detection by means of
enzyme-linked 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.
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.10Imaging
Studies Syndromes in immunocompetent hosts
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.
Pericarditis: Echocardiography demonstrates pericardial fluid,
but findings are nonspecific.
Syndromes in hosts with an underlying illness or
immunodeficiency
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 FindingsPulmonary 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 CareMost 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
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
life-threatening 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
anti-inflammatory 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
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
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 CareSurgical 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.
ConsultationsInfectious disease specialists can assist in the
differential diagnosis, in planning appropriate workup, and in
choosing therapeutic regimens, particularly for immunocompromised
patients.
ActivityBed 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 agentsSystemic 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.11Echinocandins (eg, caspofungin) should not be used.
Drug NameAmphotericin B (Amphocin, Fungizone)
DescriptionProduced 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 Dose1 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 Dose0.1 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
ContraindicationsDocumented hypersensitivity
InteractionsAntineoplastic agents may enhance potential for
renal toxicity, bronchospasm, and hypotension; corticosteroids,
digitalis, and thiazides may potentiate hypokalemia; cyclosporine
increases risk of renal toxicity
PregnancyB - Usually safe but benefits must outweigh the
risks.
PrecautionsCaution 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
histoplasmosisMonitor 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 dHypoxemia, 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, azolesThe 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, 13Posaconazole 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 NameItraconazole (Sporanox)
DescriptionSynthetic triazole antifungal agent. Can be used in
CPH, but relapse rate higher than with amphotericin B.
Adult Dose200 mg PO qd, may increase by increments of 100 mg/d;
not to exceed 400 mg/d divided bid
Pediatric DoseNot established, limited data suggest 3-5 mg/kg/d
PODisseminated histoplasmosis: 6-8 mg/kg/d POProphylaxis in
children with HIV infection: 2-5 mg/kg PO q12-48h
ContraindicationsDocumented hypersensitivity; CNS
histoplasmosis
InteractionsInhibits 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-beta-methylglutarylcoenzyme A (HMG-CoA) reductase
inhibitors (lovastatin or simvastatin); coadministration with
cisapride can cause cardiac rhythm abnormalities and deathMay
increase digoxin levels; coadministration may increase plasma
levels of midazolam and triazolam; phenytoin and rifampin may
reduce levels (may alter phenytoin metabolism)
PregnancyC - Safety for use during pregnancy has not been
established.
PrecautionsCaution in hepatic impairment (monitor liver
function); concomitant use of CYP substrates with decreased
clearance (eg, cisapride) may result in toxicity
Drug NameKetoconazole (Nizoral)
DescriptionSynthetic imidazole antifungal agent. Can be used for
CPH, but relapse rate higher than that of amphotericin B.
Adult Dose200-400 mg PO qd/bid
Pediatric Dose3.3-6.6 mg/kg PO qd
ContraindicationsDocumented hypersensitivity; concomitant use
with CYP substrates with decreased clearance (eg, cisapride) may
result in toxicity
InteractionsPotent 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
PregnancyC - Safety for use during pregnancy has not been
established.
PrecautionsEfficacy against H capsulatum less well established
than with amphotericin B and itraconazole (use only as alternative
to these agents); hepatotoxicity may occur
Drug NameFluconazole (Diflucan)
DescriptionSynthetic triazole antifungal with low plasma protein
binding. CNS penetration better than that of imidazoles.
Adult Dose400 mg/d PO/IV for CNS histoplasmosis or for
prophylaxis in immunosuppressed patients
Pediatric Dose12 mg/kg/d IV/PO; not to exceed 600 mg/d
ContraindicationsDocumented hypersensitivity
InteractionsInhibits 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
PregnancyC - Safety for use during pregnancy has not been
established.
PrecautionsDecreased activity against H capsulatum versus other
azoles; caution in impaired renal function; periodically monitor
liver and renal function
Drug NamePosaconazole (Noxafil)
DescriptionTriazole 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 Dose200 mg (5 mL) PO tid with food or liquid nutritional
supplement to enhance absorption
Pediatric Dose13 years: Administer as in adults
ContraindicationsDocumented hypersensitivity; coadministration
with ergot alkaloids; coadministration with CYP3A4 substrates (eg,
terfenadine, astemizole, cisapride, pimozide, halofantrine,
quinidine) likely to cause serious toxicities
InteractionsMetabolized by means of uridine diphosphate (UDP)
glucuronidation; P-glycoprotein (P-gp) efflux substrate; CYP3A4
inhibitorUDP 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)
PregnancyC - Safety for use during pregnancy has not been
established.
PrecautionsCommon 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: NSAIDsNSAIDs 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 NameNaproxen (Aleve, Naprosyn)
DescriptionFor relief of mild to moderate pain; inhibits
inflammatory reactions and pain by decreasing activity of
cyclooxygenase, which is responsible for prostaglandin
synthesis.
Adult Dose250-500 mg PO bid; may increase to 1.5 g/d for limited
periods
Pediatric Dose2 years: 2.5 mg/kg PO q12h; may increase dose, not
to exceed 10 mg/kg/d
ContraindicationsDocumented hypersensitivity; peptic ulcer
disease; recent GI bleeding or perforation; renal insufficiency
InteractionsCoadministration 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
PregnancyB - Usually safe but benefits must outweigh the
risks.
PrecautionsCategory 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 NameIbuprofen (Motrin, Advil, Ibuprin)
DescriptionInhibits inflammatory reactions and pain by
decreasing prostaglandin synthesis.
Adult Dose400 mg PO q4-6h, 600 mg q6h, or 800 mg q8h while
symptoms persist; not to exceed 3.2 g/d
Pediatric Dose20-70 mg/kg/d PO divided tid/qid; start at lower
end of dosing range and titrate; not to exceed 2.4 g/d
ContraindicationsDocumented hypersensitivity; peptic ulcer
disease, recent GI bleeding or perforation, renal insufficiency, or
high risk of bleeding
InteractionsCoadministration 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
PregnancyB - Usually safe but benefits must outweigh the
risks.
PrecautionsCategory 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
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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
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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
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References
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