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Pulmonology
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HistoplasmosisLast Updated: March 31,
2006 |
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| Synonyms and related keywords:
Histoplasma capsulatum, Histoplasma, fungal pneumonia,
tuberculosis, Darling disease, Darling's disease, fibrosing
mediastinitis |
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AUTHOR INFORMATION
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Section 1 of 11
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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
Coauthor(s): Gulnur
Com, MD, Fellow in Pediatric Pulmonology, Department of
Pediatrics, Division of Pulmonary Medicine, University of Alabama School of
Medicine
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| James S Hagood, MD, is a member of the following medical
societies: American Thoracic
Society
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| Editor(s): 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; and Russell W
Steele, MD, Professor and Vice Chairman, Department of
Pediatrics, Head, Division of Infectious Diseases, Louisiana State
University Health Sciences Center |
Disclosure
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INTRODUCTION |
Section 2 of 11   |
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Background:
Histoplasmosis is caused by infection with the dimorphic soil
fungus Histoplasma capsulatum. Histoplasmosis is endemic in the
central United States and in other parts of the world with warm humid soil
and large migratory bird populations. 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 host
immunity and inoculum size.
The principal challenges to the clinician caring for patients with
histoplasmosis are to recognize the disease, which can mimic a number of
other processes, and to rationally use a confusing array of diagnostic
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 a large number of patients with abnormal chest
radiographs but negative tuberculin test results actually had self-limited
infection with histoplasmosis.
Pathophysiology: Five serotypes of H
capsulatum exist, including some avirulent strains.
Histoplasma species exist in mycelial form at ambient
temperatures. The spores of H capsulatum (microconidia) become
airborne when soil is disturbed. High numbers of spores exist in
microfoci, in which soil is contaminated heavily with bird or bat
droppings, such as under bird roosts or in caves (see Image 4).
Urban and suburban outbreaks in endemic areas often are associated with
large-scale construction or cleaning projects in which soil is disturbed.
The microconidia (1-5 mm in diameter) are inhaled
easily and deposited in distal air spaces. At body temperature,
proliferation of the yeast (infective) form of the organism occurs within
3-5 days.
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 for killing
of the organisms. Specific helper T cells are able to activate macrophages
to form the granulomas that are characteristic of the disease.
Extracellular killing is mediated by natural killer cells and enhanced by
the presence of antibodies.
Pneumonitis, with a predominant mononuclear infiltrate, peaks 2 weeks
after infection. Granulomas can form in the pulmonary parenchyma and in
hilar and mediastinal lymph nodes. These 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 noted following
asymptomatic infection. In individuals with impaired T cell–mediated
immunity, other sites of infection include bone marrow, liver, adrenal
glands, CNS, joint spaces, heart valves, and blood vessels. Reports exist
of infectious complications in almost every tissue. Reactivation of
infection may occur in individuals who become immunosuppressed long after
a primary infection, accounting for many of the cases observed in
nonendemic areas. Reinfection can occur in the setting of heavy conidial
burdens but is generally mild because of specific immunity.
Frequency:
- In the US: An estimated 50 million individuals have
been infected with H capsulatum. Nationwide, approximately 22%
of the population have positive skin test results for histoplasmin,
although, in endemic areas in the central United States (specifically,
the Ohio and Mississippi River valleys, see Image 2),
this rate may be as high as 80%. Of the 500,000 individuals who are
exposed annually, 50,000-200,000 develop symptoms, and 1500-4000 require
hospitalization.
- Internationally: Endemic regions for histoplasmosis
are found in Central and South America, the Caribbean, Africa, and Asia;
however, microfoci are believed to occur anywhere soil conditions are
appropriate to harbor growth of H capsulatum.
Mortality/Morbidity: The overall mortality rate of
histoplasmosis is low; most cases resolve spontaneously. In
immunosuppressed individuals, progressive disseminated disease has a high
mortality rate (7-23%). Without treatment, disseminated disease is usually
fatal. Disseminated infection can localize in any tissue, leading to a
variety of complications. Pericarditis and obstruction of mediastinal
structures are the principal complications in immunocompetent individuals.
Race: No apparent race predilection to infection or
disease presentation exists.
Sex: In adults, histoplasmosis has been described more
commonly in men than in women; however, certain clinical manifestations,
such as erythema nodosum, have been described more 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 immunodeficiency exists. The incidence of disseminated
histoplasmosis in children appears to have decreased in the last 30 years.
History: Clinical
presentation varies, depending on the inoculum size, the host immune
status, and presence of underlying lung disease. Overt symptoms occur in
5% of individuals following low-level exposure, but the rate of a clinical
disease exceeds 75% following heavy exposure in normal hosts. The
incubation time of acute histoplasmosis in previously nonimmune
individuals ranges between 9 and 17 days.
In 80% of cases, the symptoms are nonspecific and include fever,
chills, myalgias, and nonproductive cough and chest pain. This acute
syndrome can range from mild (lasting 1-5 d) to severe (lasting 10-21 d,
with associated weight loss, fatigue, and night sweats). Fatigue may
persist for weeks after the resolution of acute symptoms.
- Syndromes in immunocompetent hosts
- Severe acute pulmonary syndrome: Following a large inoculum,
patients may develop severe acute pulmonary syndrome, characterized by
a flu-like prodrome with high fever, chills, fatigue, cough, and chest
pain followed by dyspnea and hypoxemia, which may progress to an adult
respiratory distress syndrome (ARDS)-like illness (see Image
5).
- Histoplasmoma: Occasionally, histoplasmosis presents as a single
pulmonary parenchymal nodule, observed as a coin lesion on chest
radiography. These are often asymptomatic.
- Mediastinal obstructive syndromes (granulomatous mediastinitis)
- Enlargement of mediastinal lymph nodes occurs in most cases of
histoplasmosis (see Image
1). In 5-10% of patients with acute pulmonary syndromes, these
may be large enough to cause obstruction of contiguous structures,
such as airways, esophagus, and large blood vessels. Airway
obstruction can present with dry or productive cough and dyspnea.
Rarely, erosion of infected nodes into airway walls can lead to
hemoptysis, air leak syndromes, broncholithiasis, or lithoptysis.
- Esophageal obstruction can produce dysphagia. Airway-esophageal
fistulas have been reported as a complication of mediastinal
involvement with histoplasmosis. Obstruction of the pulmonary
arteries can produce symptoms of mitral valve obstruction. Fibrosing
mediastinitis is a late complication of mediastinal granuloma, in
which a 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 prior episode of
histoplasmosis, and it has been suggested that certain individuals
are predisposed to excessive fibrotic responses to
Histoplasma antigens. The lack of response to antifungal
treatment and rare isolation of H capsulatum tissue samples
indicate that an ongoing infection is not likely to play a
significant role. Presenting symptoms can include cough, dyspnea,
wheezing, hemoptysis, dysphagia, and superior vena cava (SVC)
obstructivesyndrome. 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 up to 10% of patients with
symptomatic acute disease. Occasionally, pericarditis with true
infection of the pericardium occurs in disseminated
histoplasmosis.
- Rheumatologic syndrome: A syndrome of arthritis, arthralgias, and
erythema nodosum is observed in up to 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, 6.3% of patients
exhibited rheumatologic symptoms, primarily arthritis or arthralgia.
Of these, 46% had erythema nodosum.
- Syndromes in hosts with an underlying illness or
immunodeficiency
- Chronic pulmonary histoplasmosis (CPH): This occurs most commonly
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 experience 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)
- This can occur in immunocompetent infants but is more likely in
patients with underlying disorders of cell-mediated immunity. In the
past 20 years, AIDS has become the most common underlying disorder
associated with PDH in adults, although the incidence of PDH in
children with AIDS is still low (0.4%). Disseminated histoplasmosis
in a patient with HIV can be an AIDS-defining illness. PDH also
occurs in individuals with Hodgkin disease, lymphoreticular
malignancies, and in the setting of immunosuppressive therapy.
- In children, the incidence of disseminated histoplasmosis
appears to have decreased in the last 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 high fever, GI symptoms,
hepatosplenomegaly, and pancytopenia.
- Multiorgan system failure and coagulopathy can ensue rapidly.
Adrenal involvement is common in PDH (80-90% of patients), and 15%
of patients manifest overt adrenal insufficiency.
- Local manifestations of disseminated disease: Histoplasmosis may
include genital ulcers, epididymitis, orchitis, cystitis,
cholecystitis, pancreatitis, soft tissue nodules, panniculitis, carpal
tunnel syndrome, osteomyelitis, arthritis, and hypercalcemia. The
occurrence of ocular histoplasmosis is controversial because this
clinical entity has been described in patients who reside exclusively
in areas that are nonendemic for histoplasmosis.
- Central nervous system (CNS) histoplasmosis: Meningitis
complicates 10% of disseminated cases but occurs occasionally in
immunocompetent patients. Symptoms are usually indolent and chronic,
such as fever, headache, and mental status changes. Seizures and focal
neurologic deficits can occur. Localized lesions in the brain occur in
one third of patients with CNS involvement.
- Adrenal disease might occur several years after the initial
episode as a manifestation of relapsing histoplasmosis. 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 has been reported in 4% of patients with disseminated
histoplasmosis, and mostly presents with embolic episodes.
Physical:
- 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.
- 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, such as cyanosis and digital clubbing.
- PDH: Patients usually have respiratory distress, inanition,
cachexia, pallor, and hepatosplenomegaly. Subcutaneous nodules may be
present, as well as 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 exist in microfoci, in which soil is
contaminated heavily with bird or bat droppings, such as under bird
roosts or in caves (see Image
4).
- Urban and suburban outbreaks in endemic areas often are associated
with large-scale construction or cleaning projects in which soil is
disturbed.
- The microconidia (1-5 mm in diameter) are
inhaled easily and deposited in distal air spaces.
- Histoplasmosis can occur in almost all mammals. Although the fungus
thrives in bird droppings, birds are not infected. Bats, however, can be
infected with H capsulatum. Direct animal-to-human or
human-to-human transmissions are not thought to occur.
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DIFFERENTIALS |
Section 4 of 11 |
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Blastomycosis
Coccidioidomycosis
Pneumonia
Respiratory
Distress Syndrome
Sarcoidosis
Tuberculosis
Other Problems to be Considered:
Lung cancer
Lung Abscess
Lymphoma
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Lab Studies:
- The laboratory diagnosis of fungal disease in general and of
histoplasmosis particularly is challenging because of the nonspecific
clinical findings, the difficulty of culturing organisms, and the
confusing array of diagnostic tests available. MiraVista Diagnostics
laboratory has established a web site to assist clinicians (see MiraVista
Diagnostics).
- General laboratory findings in disseminated disease include
pancytopenia, elevated liver enzymes, hyperbilirubinemia, and elevated
serum LDH levels.
- Silver stain of tissue sections or Wright stain of peripheral
blood/bone marrow aspirate smears are useful to diagnose patients with
acute disseminated infection or severe pulmonary
infection.
- 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 up to 12 weeks. A DNA probe for H capsulatum
permits rapid identification.
- Blood culture using the lysis-centrifugation system is somewhat
more rapid and increases sensitivity.
- Cultures are positive in up to 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.
- Multiple specimens increase yield.
- Skin testing: Histoplasmin skin testing is not recommended for
diagnostic purposes because of the high rate of positive reactions in
endemic areas, the variable duration of skin test responses, and the
possibility that skin testing can affect subsequent serologic tests. It
has been useful as an epidemiologic tool.
- A number of tests have been developed to detect the presence of
H capsulatum antigen or to detect host antibody to infection.
Tests used to detect host antibody to infection are more commonly
employed clinically. 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 enabling rapid
diagnosis by antigen detection. Because of lower fungal burden in
patients with mild manifestations, the yield of antigen detection is
low.
- Antibody levels peak 6 weeks following exposure and decline over a
2- to 5-year period. Elevated antihistoplasma antibody levels might
result from a previous infection or following other types of fungal
infections.
- 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 test 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 almost 80-100% of patients with chronic
pulmonary infections.
- The CF test uses both mycelial and yeast phase antigens. An
antibody to yeast phase CF titer of more than 1:32 is consistent with
active infection in an endemic area, although an acute titer of more
than 1:8 should be considered suggestive of infection, especially in
nonendemic areas. CF has higher sensitivity than ID. In acute
pulmonary histoplasmosis, the CF test is positive in 90% of patients,
whereas the sensitivity of ID is up to 75%.
- A 4-fold rise in titer between acute and convalescent paired sera
is diagnostic. Antibodies may clear within months following 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 exists.
- Antibody responses can also be measured by enzyme immunoassay or
Western blot assay. Even though antibodies can be detected faster by
these methods than by the standard tests, these methods are difficult
to standardize, quantitate, and interpret.
- 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 higher
sensitivity, up to 90% for immunocompetent patients with disseminated
or acute pulmonary disease. BAL fluid antigen levels can be higher
than in blood or urine, and matched BAL, urine, and serum specimens
have the highest yield.
- The recommended approach is first to perform antigen testing on
blood and urine on a patient with suspected histoplasmosis. Then, the
focus in testing will depend on the symptoms; for example, in patients
with respiratory symptoms, obtain BAL; in those with CNS symptoms,
obtain CSF.
- Cross-reactivity with other endemic mycoses exists.
- If initially positive, the antigen test can be used to monitor
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 continued
antifungal therapy. Antigen levels rise during relapse, enabling
detection in patients whose antifungal treatment has been
discontinued.
- Recently, Histoplasma antigen detection by ELISA has
become available for different specimens including serum, urine, BAL,
and CSF. The sensitivity of this test has been reported to be as high
as 92% in urine specimens and 82% in serum specimens from patients
with disseminated histoplasmosis. Even though the sensitivity is low
in self-limited and chronic pulmonary histoplasmosis, the specificity
is as high as 98%.
- Molecular diagnostics
- Preliminary studies suggest that PCR might improve the accuracy of
identification of H capsulatum in tissue specimens. DNA
probes are also commercially available and used for definitive
identification of positive culture.
- A retrospective review of pediatric cancer patients at St Jude's
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.
Imaging 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, often can be
observed on plain chest radiographs (see Image
1). In fibrosing mediastinitis, roentgenographic findings can be
subtle, such as superior mediastinal widening or carinal splaying (see
Image
6). CT scan better demonstrates the extent of mediastinal
involvement. 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 densities, 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 scan or MRI.
Other Tests:
- Pulmonary function testing may demonstrate fixed or variable airway
obstructive patterns in mediastinal obstructive syndromes. Acute
pulmonary disease is more likely to demonstrate a restrictive
pattern.
Procedures:
- Pericardiocentesis: Pericarditis may occur in 10% of patients who
are symptomatic. Pericardiocentesis yields bloody sterile pericardial
fluid.
- 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 of affected tissues can be performed via open procedures or
thoracoscopy.
- Lumbar puncture in CNS histoplasmosis demonstrates a lymphocytic
pleocytosis, with elevated protein and normal or low
glucose.
Histologic Findings: Pulmonary
histoplasmosis has a predominantly mononuclear infiltrate. Multiple
granulomas are characteristic, with multinucleated giant cells. Larger
granulomas often are caseating. The periphery of granulomas may show
fibrosis, and calcification of central areas may be present. On
hematoxylin and eosin (H and E) 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.
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TREATMENT |
Section 6 of 11 |
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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 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 significant dyspnea or
hypoxemia. After discharge from the hospital, itraconazole should be
used to complete a 12-week course of antifungal therapy. Patients with
less severe manifestations can be treated with itraconazole only, and
treatment should be continued for 3 months. Corticosteroids also have
been used for short-term therapy (tapered over a 2-wk period);
however, these agents always should be used with caution in fungal
infections because the risk of impaired cell-mediated immunity exists
with prolonged use.
- Mediastinal obstructive syndromes: For patients with significant
symptomatic obstructive symptoms, antifungal treatment should be
initiated. Reports exist of 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 fails to improve after 4-6 weeks of
antifungal treatment. Surgical interventions do not prevent
progression to fibrosing mediastinitis. Although reports exist of
successful surgical management of fibrosing mediastinitis, the
operative mortality rate is high, and surgeons inexperienced in the
management of 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 has been
described but is rare.
- Rheumatologic syndrome: This often resolves without treatment or
with a brief course of NSAIDs.
- Syndromes in hosts with an underlying illness or
immunodeficiency
- Chronic pulmonary syndrome (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 a period of at
least 3 months. Relapse rates are higher (10-15%) with the latter 2
agents. Fluconazole is less effective. The preferred treatment is
amphotericin B followed by itraconazole for 12-24 months.
- PDH: Amphotericin B significantly reduces the mortality rate of
PDH. It has been recommended that a cumulative dose of at least 35
mg/kg be administered to prevent relapse, but many patients have been
treated successfully with a change to oral agents after initial
improvement of symptoms on 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 of the cases, but relapse may occur. Treatment with
fluconazole is discouraged because of its reduced efficacy as chronic
maintenance therapy for histoplasmosis.
- 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
infections complicated by fistulas, hemoptysis, or broncholithiasis. The
surgical management of mediastinal obstructive syndromes is more
controversial because they may improve with observation or medical
management. Severe obstruction of airways or large blood vessels may be
life threatening and require immediate intervention. 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, planning appropriate workup, and
choosing therapeutic regimens, particularly in immunocompromised patients.
Activity: Bed rest has been recommended for systemic
syndromes.
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MEDICATION |
Section 7 of 11 |
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Always consult the latest information
regarding drugs of choice, dosage, and administration. Consultation by
infectious diseases specialists can be very 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 has potential side effects. New
lipid formulations of amphotericin B have less renal toxicity; however,
their cost is much higher, and it is not proven that they have higher
efficacy. A double blind randomized trial comparing liposomal amphotericin
B (L-AMB) to standard formulation (AmB) in patients with AIDS showed that
L-AMB was at least as effective as AmB, with marked reduction in renal
toxicity.
Caspofungin is a new lipopeptide antifungal agent, and has been studied
in vitro and in animal models of histoplasmosis. Current reports are
equivocal in terms of susceptibility and clinical response in animal
models of histoplasmosis. This drug is currently approved for the
treatment of esophageal and invasive candidiasis and for invasive
aspergillosis. It has low toxicity and has been used in combination with
L-AMB for seriously ill patients with the infections mentioned above.
Drug Name
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Amphotericin B (Amphocin,
Fungizone) -- Produced by a strain of Streptomyces nodosus;
can be fungistatic or fungicidal. Binds to sterols, such as
ergosterol, in the 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, followed by
daily increased dose by 0.5-1 mg/kg/d; not to exceed 1.5 mg/kg/d;
infuse IV over 2-6 h
|
| Pediatric Dose |
0.1 mg/kg IV test dose; if
tolerated, administer additional 0.4 mg/kg the same day; daily
increased dose by 0.5-1 mg/kg/d; not to exceed 1.5 mg/kg/d
|
| Contraindications |
Documented hypersensitivity
|
| Interactions |
Antineoplastic agents may enhance
the potential of amphotericin B for renal toxicity, bronchospasm,
and hypotension; corticosteroids, digitalis, and thiazides may
potentiate hypokalemia; the risk of renal toxicity is increased with
cyclosporine
|
| Pregnancy |
B - Usually safe but benefits must
outweigh the risks.
|
| Precautions |
Use with caution in renal
impairment; monitor BUN and creatinine every other day as dose
increases; amphotericin B lipid or liposomal preparations may be
tolerated better in patients with renal disease or intolerance of
standard preparations; may offer the theoretical advantage of higher
tissue levels; use in comparison to standard preparations for
histoplasmosis currently is being studied
Monitor renal
function, serum electrolytes (eg, magnesium, potassium), liver
function, CBC, and hemoglobin concentrations; resume the therapy at
the lowest level (eg, 0.25 mg/kg) when the therapy is interrupted
for more than 7 d; hypoxemia, acute dyspnea, and interstitial
infiltrates may occur in neutropenic patients receiving leukocyte
transfusions (separate time of amphotericin infusion from time of
leukocyte transfusion); fever and chills are not uncommon after
first few administrations of drug; rare acute reactions may include
hypotension, bronchospasm, arrhythmias, and shock | |
Drug Name
|
Caspofungin (Cancidas) -- First of
a new class of antifungal drugs (glucan synthesis inhibitors).
Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of
fungal cell wall.
|
| Adult Dose |
70 mg IV over 1 h on day 1; 50 mg
IV qd thereafter
|
| Pediatric Dose |
Not established
|
| Contraindications |
Documented hypersensitivity
|
| Interactions |
Coadministration with cyclosporine
may increase risk of hepatotoxicity; carbamazepine, nelfinavir,
efavirenz, or dexamethasone may decrease levels of caspofungin;
caspofungin may decrease levels of tacrolimus; rifampin decreases
caspofungin levels by 30% (ie, adjust dose to 70 mg/d)
|
| Pregnancy |
C - Safety for use during pregnancy
has not been established.
|
| Precautions |
Caution in moderate hepatic
dysfunction (ie, decrease dose to 35 mg/d); may exacerbate
preexisting renal dysfunction or
myelosuppression | Drug Category:
Antifungal agents, azoles -- The azole antifungal agents
are divided into 2 groups: imidazoles and triazoles. The imidazoles are an
older group including miconazole, ketoconazole, and clotrimazole. The
triazoles consist of fluconazole, itraconazole, and new second-generation
azoles ravuconazole (investigational in the United States), voriconazole,
and posaconazole (investigational in the United States).
Itraconazole is more effective than ketoconazole or fluconazole for
treatment of histoplasmosis. It is also very 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; however, the
use of these agents in the treatment of histoplasmosis has not been
adequately studied. In vitro, the fungistatic effect of voriconazole is
similar to that of itraconazole against H capsulatum.
Drug Name
|
Itraconazole (Sporanox) --
Synthetic triazole antifungal agent. Can be used in chronic
pulmonary histoplasmosis, but relapse rate higher than for
amphotericin B.
|
| Adult Dose |
200 mg PO qd, may increase by 100
mg/d increments; not to exceed 400 mg/d divided bid
|
| Pediatric Dose |
Not established, limited data
suggest: 3-5 mg/kg/d PO
Disseminated histoplasmosis: 6-8
mg/kg/d PO
Prophylaxis in children with HIV: 2-5 mg/kg PO
q12-48h
| Contraindications |
Documented hypersensitivity;
concomitant use of CYP450 substrates where their decreased clearance
may result in toxicity (eg, cisapride)
|
| Interactions |
Inhibits CYP450 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 are used; rhabdomyolysis may
occur with coadministration of 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
itraconazole levels (phenytoin metabolism may be altered)
| Pregnancy |
C - Safety for use during pregnancy
has not been established.
|
| Precautions |
Caution in hepatic impairment
(monitor LFTs); do not use for CNS histoplasmosis | | |
Drug Name
|
Ketoconazole (Nizoral) -- A
synthetic imidazole antifungal agent. Can be used for CPH, but has a
higher relapse rate than amphotericin B.
|
| Adult Dose |
200-400 mg PO qd/bid
|
| Pediatric Dose |
3.3-6.6 mg/kg PO qd
|
| Contraindications |
Documented hypersensitivity;
concomitant use with CYP450 substrates where their decreased
clearance may result in toxicity (eg, cisapride)
|
| Interactions |
Potent CYP450 3A4 inhibitor;
isoniazid may decrease bioavailability of ketoconazole;
coadministration decreases effects of rifampin and ketoconazole; may
increase effect of anticoagulants; may increase toxicity of
corticosteroids and cyclosporine (adjust cyclosporine dose); may
decrease theophylline levels; administer antacids, anticholinergics,
or H2 blockers at least 2 h after taking ketoconazole
|
| Pregnancy |
C - Safety for use during pregnancy
has not been established.
|
| Precautions |
Efficacy against H
capsulatum is less well established than with amphotericin B
and itraconazole; therefore, use only as an alternative to these
agents; hepatotoxicity may occur |
Drug Name
|
Fluconazole (Diflucan) -- Synthetic
triazole antifungal with low plasma protein binding and better CNS
penetration than 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 CYP450 3A4; levels may
increase with hydrochlorothiazide; fluconazole levels may decrease
with long-term coadministration of rifampin; coadministration of
fluconazole may decrease phenytoin clearance; may increase
concentrations of theophylline, tolbutamide, glyburide, and
glipizide; coadministration may increase effects of anticoagulants;
increases in cyclosporine concentrations may occur when administered
concurrently
|
| Pregnancy |
C - Safety for use during pregnancy
has not been established.
|
| Precautions |
Better CNS penetration than other
azoles, but less activity against H capsulatum; use with
caution in impaired renal function; monitor liver and renal function
periodically | Drug Category:
Nonsteroidal anti-inflammatory agents (NSAIDs) -- Have
analgesic, antiinflammatory, and antipyretic activities. Their mechanism
of action is not known, but may inhibit cyclooxygenase activity and
prostaglandin synthesis. Other mechanisms also may exist, such as
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
|
Ibuprofen (Motrin, Advil, Ibuprin)
-- 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
|
| Contraindications |
Documented hypersensitivity; peptic
ulcer disease, recent GI bleeding or perforation, renal
insufficiency, or high risk of bleeding
|
| Interactions |
Coadministration with aspirin
increases risk of inducing serious NSAID-related side effects;
probenecid may increase concentrations and, possibly, toxicity of
NSAIDs; may decrease effect of hydralazine, captopril, and
beta-blockers; may decrease diuretic effects of furosemide and
thiazides; may increase PT when taking anticoagulants (instruct
patients to watch for signs of bleeding); may increase risk of
methotrexate toxicity; phenytoin levels may be increased 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 |
Drug Name
|
Naproxen (Aleve, Naprosyn) -- For
relief of mild to moderate pain; inhibits inflammatory reactions and
pain by decreasing activity of cyclo-oxygenase, 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
| Contraindications |
Documented hypersensitivity; peptic
ulcer disease; recent GI bleeding or perforation; renal
insufficiency
|
| Interactions |
Coadministration with aspirin
increases risk of inducing serious NSAID-related side effects;
probenecid may increase concentrations and, possibly, toxicity of
NSAIDs; may decrease effect of hydralazine, captopril, and
beta-blockers; may decrease diuretic effects of furosemide and
thiazides; may increase PT when taking anticoagulants (instruct
patients to watch for signs of bleeding); may increase risk of
methotrexate toxicity; phenytoin levels may be increased 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 risk acute renal failure; leukopenia occurs rarely, is
transient, and usually returns to normal during therapy; persistent
leukopenia, granulocytopenia, or thrombocytopenia warrants further
evaluation and may require discontinuation of drug | |
| |
FOLLOW-UP |
Section 8 of 11 |
|
|
Prognosis:
- Most cases of histoplasmosis resolve spontaneously 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.
| |
MISCELLANEOUS |
Section 9 of 11 |
|
|
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.
| |
PICTURES |
Section 10 of
11 |
|
|
| |
BIBLIOGRAPHY |
Section 11 of
11 |
|
|
- Adderson EE: Histoplasmosis in a pediatric oncology center. J
Pediatr 2004 Jan; 144(1): 100-6[Medline].
- Antachopoulos C, Walsh TJ: New agents for invasive mycoses in
children. Curr Opin Pediatr 2005 Feb; 17(1): 78-87[Medline].
- Edwards LB, Acquaviva FA, Livesay VT, et al: An atlas of sensitivity
to tuberculin, PPD-B, and histoplasmin in the United States. Am Rev
Respir Dis 1969 Apr; 99(4): Suppl:1-132[Medline].
- George R, Penn R: Histoplasmosis. In: Sarosi GA, Davies SF, eds.
Fungal Diseases of the Lung. 1993; 39-50.
- Guimaraes AJ, Pizzini CV, De Matos Guedes HL: ELISA for early
diagnosis of histoplasmosis. J Med Microbiol 2004 Jun; 53(Pt 6):
509-14[Medline].
- Hamilton AJ: Serodiagnosis of histoplasmosis, paracoccidioidomycosis
and penicilliosis marneffei; current status and future trends. Med Mycol
1998 Dec; 36(6): 351-64[Medline].
- Joseph Wheat L: Current diagnosis of histoplasmosis. Trends
Microbiol 2003 Oct; 11(10): 488-94[Medline].
- Kumar N, Singh S, Govil S: Adrenal histoplasmosis: clinical
presentation and imaging features in nine cases. Abdom Imaging 2003
Sep-Oct; 28(5): 703-8[Medline].
- Kurowski R, Ostapchuk M: Overview of histoplasmosis. Am Fam
Physician 2002 Dec 15; 66(12): 2247-52[Medline].
- Levitz SM: Overview of host defenses in fungal infections. Clin
Infect Dis 1992 Mar; 14 Suppl 1: S37-42[Medline].
- Mathisen DJ, Grillo HC: Clinical manifestation of mediastinal
fibrosis and histoplasmosis. Ann Thorac Surg 1992 Dec; 54(6): 1053-7;
discussion 1057-8[Medline].
- Mocherla S, Wheat LJ: Treatment of histoplasmosis. Semin Respir
Infect 2001 Jun; 16(2): 141-8[Medline].
- Murray JF, Nadel JA: Histoplasmosis. Textbook of Respiratory
Medicine, 4th ed. 2005; 1045-1055.
- O'Shaughnessy EM, Shea YM, Witebsky FG: Laboratory diagnosis of
invasive mycoses. Infect Dis Clin North Am 2003 Mar; 17(1): 135-58[Medline].
- Wheat J: Histoplasmosis. Experience during outbreaks in Indianapolis
and review of the literature. Medicine (Baltimore) 1997 Sep; 76(5):
339-54[Medline].
- Wheat J, Sarosi G, McKinsey D: Practice guidelines for the
management of patients with histoplasmosis. Infectious Diseases Society
of America. Clin Infect Dis 2000 Apr; 30(4): 688-95[Medline].
- Wheat LJ, Kauffman CA: Histoplasmosis. Infect Dis Clin North Am 2003
Mar; 17(1): 1-19, vii[Medline].
- Wiedermann BL: Histoplasmosis. In: Feigin RD, Cherry JD, Fletcher J,
eds. Textbook of Pediatric Infectious Diseases. Philadelphia, Pa: WB
Saunders and Co; 1998: 2337-2350.
| NOTE:
|
| Medicine is a constantly
changing science and not all therapies are clearly established. New
research changes drug and treatment therapies daily. The authors,
editors, and publisher of this journal have used their best efforts
to provide information that is up-to-date and accurate and is
generally accepted within medical standards at the time of
publication. However, as medical science is constantly changing and
human error is always possible, the authors, editors, and publisher
or any other party involved with the publication of this article do
not warrant the information in this article is accurate or complete,
nor are they responsible for omissions or errors in the article or
for the results of using this information. The reader should confirm
the information in this article from other sources prior to use. In
particular, all drug doses, indications, and contraindications
should be confirmed in the package insert. FULL DISCLAIMER
|
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