Aspergillus is a ubiquitous mold
that usually causes disease in immunocompromised hosts. Most infections are
caused by Aspergillus fumigatus, but
species such as A flavus and A niger are also occasionally pathogenic.
Pulmonary manifestations include allergic, saprophytic, and invasive
Allergic forms of aspergillosis result from an immunological
reaction directed against Aspergillus antigens
that are inhaled into the upper and lower respiratory tract. No
direct tissue invasion occurs. The allergic response in allergic
bronchopulmonary aspergillosis is IgE mediated. Aspergillus takes
a saprophytic form when it colonizes a preexisting lung cavity or
the airways of children with cystic fibrosis and bronchiectasis.
A mass of hyphae, an aspergilloma, forms within the cavity. Invasive
aspergillosis, the most severe form of disease, occurs predominantly
in immunocompromised patients. Invasive infection generally complicates
neutropenia or defective neutrophil function, as seen in patients
with hematological cancer or bone marrow transplantation. However, other
conditions also pose a risk for infection including solid organ
transplantation, chronic steroid use, systemic lupus erythematosus,
and HIV infection.
Bronchopulmonary Aspergillosis (ABPA)
Aspergillus does not cause invasive
disease, but rather the presence of Aspergillus,
usually A fumigatus, in the airways
stimulates an allergic response. Bronchospasm or asthma-like symptoms
result from IgE-mediated type 1 hypersensitivity reactions. ABPA
may worsen the bronchospasm of preexisting asthma or complicate
cystic fibrosis. Low grade fever, dyspnea, wheezing, and cough are
common symptoms. Affected patients frequently expectorate brown
The saprophytic form of aspergillosis is referred to as an aspergilloma
when Aspergillus colonizes a preexisting
lung cavity, such as from old tuberculosis, histoplasmosis, healed
lung abscess, or sarcoidosis. Aspergillus spores,
after being inhaled into a lung cavity, replicate and mix with fibrin,
mucous, and cellular debris forming a fungus ball. Children and
adolescents with cystic fibrosis may develop Aspergillus colonization
of bronchiectatic airways. Aspergillomas are often asymptomatic
and detected incidentally on chest radiographs. Aspergillomas produce
symptoms when local replication leads to erosion into adjacent bronchial
arteries. Semiinvasive or invasive aspergillomas have also been described.
Symptoms in these conditions result from direct invasion into surrounding
lung parenchyma or from the inflammatory process extending into
adjacent lung tissue and pleura. The most common symptom associated
with an aspergilloma is hemoptysis, which may be mild or progressively
fatal. Life-threatening hemoptysis occurs in 20–30% of
patients. Other less severe symptoms include chest pain and cough.
Invasive pulmonary aspergillosis has an extremely high mortality
rate. Individuals with prolonged (more than 10–12 days)
and significant [absolute neutrophil count (ANC) <500
cells/mm3, especially ANC <100 cells/mm3] neutropenia
from hematological cancer or bone marrow transplantation are at
greatest risk, but other immunodeficiency disorders also predispose
to infection. Invasive aspergillosis may cause infection in any
organ after hematogenous dissemination from the lungs. However,
60% of patients have disease localized only to the lungs.
Symptoms are frequently insidious in onset, occurring over days
to months. Fever, dry cough, dyspnea, and pleuritic chest pain are
common. Other than fever, tachypnea, and sometimes hypoxia, the
physical examination is usually normal. The angioinvasiveness of Aspergillus may cause mild hemoptysis
or fatal pulmonary hemorrhage. Aspergillus may
also cause necrotizing tracheobronchitis, rhinosinusitis, or CNS
infection in high-risk patients. Symptoms of tracheobronchitis include
fever, chest pain, productive cough, and often hemoptysis.
Findings and Diagnosis
Patients with asthma and characteristic fleeting pulmonary infiltrates
or central bronchiectasis on chest radiographs may have ABPA. Other
criteria for diagnosing ABPA include peripheral eosinophilia, increased
serum IgE levels, and immediate wheal and flare skin reactivity
to Aspergillus antigens. A fumigatus or other Aspergillus species are frequently
cultured from sputum.
Finding a fungus ball within a cavity on chest radiograph or
CT is often sufficient to diagnose aspergilloma, although other
molds and sometimes bacteria may colonize cavities. Although rarely
necessary, positively identifying Aspergillus within
a lung cavity may be made by sputum culture or examination of tissue
obtained by biopsy or surgical resection.
Definitive diagnosis of invasive aspergillosis requires histopathology
that demonstrates characteristic acute-angle branching, septated
hyphae, and culture confirmation. Blood cultures are seldom positive.
Sputum cultures lack sensitivity, but have high specificity in neutropenic
patients. Sputum cultures in immunocompetent hosts are not specific
and often represent benign airway colonization. BAL fluid has high
specificity in immunocompromised patients, but sensitivity varies depending
on the underlying disease and the extent of radiographic abnormalities.
BAL fluid yields a diagnosis in 30–70% of patients
with invasive aspergillosis and underlying neutropenia. Transbronchial
biopsy may be falsely negative due to sampling error and bronchial
brushings add little to the sensitivity of BAL. Occasionally percutaneous
or open lung biopsy is required for diagnosis. The safety of these
procedures is often limited, however, by potential bleeding related to
the thrombocytopenia that frequently accompanies hematological cancers.
A presumptive diagnosis of invasive aspergillosis is frequently
made based on clinical suspicion and radiographic findings, especially
Infection is often diagnosed late because symptoms are insidious
in onset and standardized, noninvasive diagnostic tests are not
available. These factors contribute directly to the high mortality rate
observed with this infection. Promising developments have been made
recently in serodiagnosis and polymerase chain reaction (PCR)-based
methodologies. Galactomannan, a component of the cell wall of Aspergillus, can be detected by enzyme-linked
immunosorbent assay (ELISA) in the serum of patients at earlier
stages of infection. Some studies have shown good sensitivity and
specificity (>90%) of this test for early diagnosis of
invasive aspergillosis in high-risk populations. PCR-based assays
that measure Aspergillus DNA are also
under intense investigation. These non-culture-based tests, although
currently investigational in the United States, may allow earlier
initiation of therapy and improve outcomes.
Bilateral, usually upper lobe, interstitial infiltrates are often
seen on chest radiograph or CT in ABPA. These infiltrates may be
fleeting or wax and wane, depending on the severity of symptoms.
Chronic inflammation leads to central bronchiectasis and pulmonary
fibrosis. A pulmonary aspergilloma appears as a round density within
a cavity, usually apical, on chest radiograph or chest CT. A clue
to the presence of an aspergilloma is a crescent sign created by
air between the superior aspect of the aspergilloma and the wall
of the cavity. Pleural thickening may occur adjacent to peripheral
Chest radiographs are abnormal in 90% of patients with
invasive pulmonary aspergillosis, but are often nondiagnostic due
to other infections or conditions that produce similar findings.
Chest CT abnormalities precede those seen on plain radiographs.
High-resolution CT offers an advantage over routine chest CT for
earlier presumptive diagnosis of invasive aspergillosis. Radiographic findings
include diffuse interstitial infiltrates, wedge-shaped or lobar
consolidation, nodular densities, and pleural effusion. The earliest
finding may be a small pleural-based nodule with a halo sign, seen
as an area of low attenuation surrounding the nodular lesion. Late
findings include cavitation of consolidated or nodular lesions and
an “air crescent” sign, representing infarcted
and contracted lung tissue.
The primary treatment of ABPA consists of oral corticosteroids
to decrease bronchospasm and tissue inflammation. Antifungal therapy
may also play a role in treating ABPA by eradicating Aspergillus from the airways. In one
randomized, placebo-controlled trial, oral itraconazole was effective
in the treatment of ABPA and was useful as a corticosteroid-sparing
agent. ABPA patients treated with itraconazole had improved exercise
tolerance and pulmonary function, and a reduction in serum IgE levels
and steroid dose.
Asymptomatic aspergilloma generally requires no therapeutic intervention.
However, semiinvasive or invasive aspergillomas benefit from antifungal
therapy. Inhaled, intracavitary, and systemic antifungal therapies
have been tried, but data obtained from randomized, controlled trials are
lacking. Hemoptysis may be ameliorated by bronchial artery embolization.
Although bleeding often recurs after 1–2 years, it is the
treatment of choice in patients deemed poor surgical candidates
due to severe underlying diffuse lung disease. Definitive treatment
for symptomatic aspergillomas is surgical resection, particularly
when life-threatening hemoptysis develops. Surgery, however, is
associated with significant morbidity and mortality in patients
with severe chronic lung disease.
Mortality of untreated invasive aspergillosis in immunocompromised
hosts is nearly 100%; treatment is associated with a complete
or partial response in only 30%. Therefore, it is imperative
to begin systemic antifungal therapy in this population if invasive
aspergillosis is suspected. Investigation to establish the diagnosis
of invasive aspergillosis should continue even after empiric antifungal
therapy has been started.
Intravenous therapy is preferred with amphotericin B being the
standard first-line agent. Lipid-based formulations of amphotericin
B should be given to patients with underlying renal insufficiency
or intolerance to conventional amphotericin B. Lipid-based agents
are at least equivalent in efficacy to conventional amphotericin
B. To date, no prospective, randomized, controlled study has proven
superiority of the lipid preparations. It has also not been established
that higher doses (>5 mg/kg/day) of lipid-based
amphotericin B are more effective than lower doses in humans. Limited
studies suggest that itraconazole, available in both the intravenous
and oral route, may be a suitable alternative to amphotericin B.
Most clinicians initiate treatment with amphotericin B, followed
by oral itraconazole for prolonged treatment once a patient’s
condition has improved.
The echinocandins (eg, caspofungin) and extended spectrum azoles
(eg, voriconazole and posaconazole) may play a larger role in the
treatment of invasive aspergillosis in the future. These agents
may replace amphotericin B as preferred first-line therapy for invasive
aspergillosis because of better efficacy and tolerance. Results
from comparative trials are only preliminary. Another promising
area of research involves combining antifungal agents with different
mechanisms of action to improve outcome (eg, amphotericin B plus
an echinocandin or an azole plus an echinocandin). Surgical resection
of isolated pulmonary lesions has been successful in some cases,
but operative risks are significant. Adjuvant therapies, such as
colony-stimulating factors (CSF) (granulocyte-CSF or granulocyte–macrophage-CSF),
interferon-γ, or related-donor white blood cell
transfusions, enhance fungal cell killing but are not recommended
for routine use at this time.
Patterson T et al: Invasive aspergillosis: disease
spectrum, treatment practices, and outcomes. 13 Aspergillus Study
Group. Medicine 2000;79:250.
(Questionnaire-based survey; good clinical statistics on Aspergillus
Stevens DA et al: A randomized trial of itraconazole
bronchopulmonary aspergillosis. N Engl J Med 2000;342:756.
(Randomized trial suggesting patients with ABPA
treated with itraconazole
require less corticosteroid.)
Stevens DA et al: Practice guidelines for diseases caused by Aspergillus
. Infectious Diseases Society
of America. Clin Infect Dis 2000;30:696.
(A must read for anyone who treats Aspergillus
good review of diagnostic modalities.)