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North American blastomycosis is a pulmonary or disseminated fungal
infection caused by Blastomyces dermatitidis.1,2 Although
rare in children,3 the infection is often difficult
to detect unless considered in the differential diagnosis. Blastomyces
dermatitidis is a dimorphic fungus that exists as a mold
in nature and is generally acquired through the inhalation of spores
that transform to yeast in the lungs. Although isolation from natural
sources has been very difficult, growth appears to occur in acidic
soil in which there is decaying organic matter and high humidity.
Cases of blastomycosis are reported from other countries (particularly
those in central Africa), but the vast majority of cases have occurred
in the Ohio and Mississippi river basins and the southeastern United States. The
highest incidence of cases appears to occur in Wisconsin, Minnesota,
Mississippi, Kentucky, Tennessee, and Arkansas. In endemic areas,
the annual incidence of symptomatic infection is about 1 to 2 per 100,000
population. Pockets of hyperendemic regions exist where the annual
incidence of symptomatic infection may approach 40 per 100,000 population.
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Although it is clear that asymptomatic infections occur, the
distribution and extent have not been determined, because reliable
skin tests or seroepidemiologic methods are not available. When
careful immunologic studies are performed in reported outbreaks
of blastomycosis, as many as 50% of infected individuals
are asymptomatic. Most cases of symptomatic blastomycosis occur
sporadically, but there are occasional reports of small outbreaks
in communities in which as many as 15 individuals may contract infection
over a short period of time. The largest reported outbreak involved
46 school-aged children and 2 adults who were infected at a camp
in Wisconsin following exposure to a beaver dam and lodge. There
is no seasonality to B dermatitidis infections,
and infections have been reported in all age groups, including newborns.4 In
large surveillance studies of confirmed cases of blastomycosis,
pediatric patients age 19 years or less comprise 3% to
11% of all identified cases. However, the typical patient
is a male, age 25 to 50 years, who has an outdoor lifestyle. The incubation
period from exposure to primary disease is 21 to 106 days (median
45 days). However, latency with eventual reactivation disease is
probable with the finding of newly recognized infection in individuals
with no exposure to endemic areas for 3 or more years. Human-to-human
transmission is rare.
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The lungs are the usual portal of entry for B dermatitidis conidia.
Inhaled conidia elicit an inflammatory response characterized by
polymorphonuclear leukocytes (PMNs). The few conidia that survive
the initial PMN phagocytosis transform to yeast, which are more
resistant to phagocytosis by PMNs and alveolar macrophages. Response
to the replicating yeast cells results in a mononuclear infiltrate
with some granulomatous component. Spread of yeast from the lungs, although
rare, may seed any body organ. Development of cell-mediated immunity
is believed to be the primary mechanism in prevention of progressive
blastomycosis, and lymphocyte reactivity is a marker of specific
cellular immunity to B dermatitidis. Most symptoms
appear to result from progression of the primary infection.
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Clinical Manifestations
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Pulmonary disease is the most common manifestation of symptomatic
blastomycosis. In two 10-year epidemiologic studies of confirmed
cases of blastomycosis in Wisconsin and Mississippi (670 and 326
cases, respectively), 75% of the cases were isolated pulmonary
disease. Pulmonary plus extrapulmonary disease occurred in 6% to
16%, whereas isolated extrapulmonary infection occurred
in 9% to 18% of cases. In clinically apparent
primary disease, onset is insidious, resembling a mild respiratory
infection accompanied by low-grade fever, chest pain, and nonproductive
cough, often with rapid resolution. These patients are usually detected
only in an outbreak situation. As the symptoms increase in severity,
spiking fevers, productive cough, and pleuritic chest pain develop.
Subacute or chronic illness may occur with low-grade fever, productive
cough, hemoptysis, weakness, anorexia, and weight loss resembling
adult reactivation tuberculosis. Rarely, the illness may be fulminant
and resemble adult respiratory distress syndrome. Mortality is such
cases may be greater than 50%.
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Radiographic studies of the chest vary widely; there is no characteristic
feature of blastomycosis that allows easy differentiation from other
pulmonary infections. In acute cases, parenchymal infiltrates, lobar
or segmental consolidation, and interstitial infiltrates have all
been described. Large lobar infiltrates may mimic tumor. In the
more chronic form of disease, air-space and interstitial infiltrates
are seen, but masslike infiltrates, pulmonary nodules, and cavitation
are more common. Pleural effusions and hilar lymphadenitis occur
in 10% or less of cases.
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Disseminated blastomycosis is caused by hematogenous spread
of the infection from the lungs to other areas of the body. Most
frequently, the disease involves cutaneous and subcutaneous tissues
as well as bone, the central nervous system, and the urogenital
tract (only in adults). Cutaneous lesions, the most common extrapulmonary
manifestation, initially appear as benign, papulopustular verrucous
nodules with a raised irregular border often with crusting and some
drainage from an underlying abscess.5 Lesions may
also become ulcerative. The borders are usually sharp and heaped
up, and the base commonly contains exudate. As the lesion extends
peripherally, the central area heals, leaving a soft, atrophic scar.
Lytic bone lesions are the second most common extrapulmonary infection. The
vertebrae, pelvis, sacrum, skull, ribs, or long bones have been
reported most frequently, but essentially any bone may be involved. Granulomatous
lesions of the liver and spleen are found in more than 40% of
patients with disseminated disease, and the kidneys, prostate, epididymis,
bladder, and testes may be involved, causing dysuria, pyuria, and
hematuria. Central nervous system involvement may be meningitis,
but is more commonly epidural or cranial abscesses. Nearly every
body organ has been reported including lymph nodes, eyes, and retropharyngeal
soft tissue.
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Mortality from blastomycosis is dependent upon age, immune state
of the host, and the type of presenting illness. Adults older than age
65 years have a mortality rate from blastomycosis 10 times or more
that of children. Although a rare infection in immunocompromised
hosts when compared to histoplasmosis, cryptococcosis, and coccidioidomycosis,
blastomycosis has been documented to cause severe and often fatal infections
in patients with many forms of immune deficiency,6 including
those with AIDS, transplants, sarcoidosis, or therapy with corticosteroids.
Regardless of the underlying disorder, blastomycosis in immunocompromised hosts
is usually an aggressive disease, often presenting with disseminated,
multiple-organ involvement and a high, early mortality.
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Although patients may present to a physician early in the course
of infection, diagnosis is often delayed more than 30 days. Typically,
patients receive one or more courses of antibiotics for bacterial
pneumonia before blastomycosis is considered. Clinical diagnosis
must be confirmed by laboratory studies, which include microscopic
examination of smears, scrapings, aspirates, sputum, and bronchoscopic
washings for the characteristic yeast along with fungal culture.
In biopsy specimens, caseous necrosis usually is absent. Cutaneous
lesions typically reveal pseudoepitheliomatous hyperplasia and budding
yeasts in pyogranulomas that are characteristic and pathognomonic. In
hematoxylin-and-eosin tissue sections, one often finds the characteristic
yeast cells with a thick, double-refractive cell wall, but these
may be difficult to see. Therefore, routine use should be made of
special stains such as the periodic acid–Schiff and Gomori
methenamine silver stain, which may help to differentiate Histoplasma and Cryptococcus. Culture
methods can confirm the diagnosis. The infected material should
be spread on the surface of Sabouraud dextrose agar slants and incubated
at room temperature or 30°C (86°F). The yeast phase may be obtained
in culture by inoculating glucose blood agar medium and incubating
at 37°C (98.6°F). Growth occurs in 2 to 4 weeks.Because of poor
sensitivity and specificity, serologic methods such as complement
fixation and enzyme-linked immunosorbent assay (EIA) usually are
not helpful. Newer EIA tests, using more purified antigens, show
sensitivities of 80% to 88% and specificities
of 98% to 100% in proven blastomycosis. EIA titers greater
than or equal to 1:32 support the diagnosis of blastomycosis. Cross-reactivity
with antigens of other fungi, particularly Histoplasma, makes
low titers of these serologic tests difficult to interpret. Until
specific antigen or polymerase chain reaction methods are introduced,
definitive diagnosis of blastomycosis will depend on finding the
organism in tissue, body fluids, or culture.
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The prognosis for pulmonary or disseminated disease is generally
good with appropriate therapy. Untreated, widely disseminated disease
always has a poor prognosis. The treatment of choice for life-threatening
or severe disease is amphotericin B.7 Ketoconazole
and itraconazole are very effective in less severe infections in
adults, but the data on pharmacokinetics, safety, and efficacy of
these drugs for children are insufficient. Itraconazole has fewer
side effects than ketoconazole and is probably the preferred option.
Small numbers of children have been treated for 6 months with a
5 to 10 mg/kg daily dose of itraconazole. However, until
more data are available, patients treated with itraconazole who
fail to respond within 2 to 4 weeks, who have inadequate serum concentrations,
or who develop clinical deterioration, should be switched to amphotericin
B.