The Clinical Spectrum of Pulmonary

Aspergillosis*
Ayman O. Soubani, MD; and Pranatharthi H. Chandrasekar, MD

Aspergillus is a ubiquitous fungus that causes a variety of clinical syndromes in the lung, ranging
from aspergilloma in patients with lung cavities, to chronic necrotizing aspergillosis in those who
are mildly immunocompromised or have chronic lung disease. Invasive pulmonary aspergillosis
(IPA) is a severe and commonly fatal disease that is seen in immunocompromised patients, while
allergic bronchopulmonary aspergillosis is a hypersensitivity reaction to Aspergillus antigens that
mainly affects patients with asthma. In light of the increasing risk factors leading to IPA, such as
organ transplantation and immunosuppressive therapy, and recent advances in the diagnosis and
treatment of Aspergillus-related lung diseases, it is essential for clinicians to be familiar with the
clinical presentation, diagnostic methods, and approach to management of the spectrum of
pulmonary aspergillosis. (CHEST 2002; 121:1988 –1999)

Key words: allergic pulmonary aspergillosis; Aspergillus; fungal diseases; immunocompromised host; pulmonary
infection

Abbreviations: ABPA ⫽ allergic bronchopulmonary aspergillosis; BMT ⫽ bone marrow transplantation;

CNA ⫽ chronic necrotizing aspergillosis; IPA ⫽ invasive pulmonary aspergillosis

A spergillus is a ubiquitous soil-dwelling organism

found in organic debris, dust, compost, foods,
This article reviews the clinical spectrum of pul-
monary aspergillosis, emphasizing the risk factors,
spices, and rotted plants. There are approximately clinical picture, and recent advances in diagnostic
200 species of Aspergillus; however, only a few are and therapeutic approaches.
known to be pathogenic for humans. Aspergillus
fumigatus, Aspergillus flavus, and Aspergillus niger
are the most commonly encountered species, but Aspergilloma
other species, like Aspergillus terreus, Aspergillus This is the most common and best-recognized
clavatus, Aspergillus niveus, and Aspergillus nidu- form of pulmonary involvement due to Aspergillus.
lans, have rarely been reported to cause disease in The aspergilloma (fungal ball) consists of masses of
humans.1 fungal mycelia, inflammatory cells, fibrin, mucus,
Aspergillus, like other filamentous fungi, is pri- and tissue debris, usually developing in a preformed
marily acquired from an inanimate reservoir, usu- lung cavity. Although other fungi may cause the
ally by the inhalation of airborne spores. The formation of a fungal ball (for example, Zygomycetes
organism grows best at 37°C, and the small spores and Fusarium), Aspergillus spp (specifically, A fu-
(2 to 3 ␮m) are easily inhaled and deposited deep migatus) are by far the most common etiologic
in the lungs, leading to a variety of clinical syn- agents.
dromes (Fig 1). Although these are distinct pul- The true incidence of aspergilloma is not known.
monary entities, on rare occasions one condition In a study4 of 544 patients with pulmonary cavities
may change to another; for example, an aspergil- secondary to tuberculosis, 11% had radiologic
loma may change to invasive pulmonary asper- evidence of aspergilloma. The most common pre-
gillosis (IPA).2,3 disposing factor is the presence of a preexisting
lung cavity formed secondary to tuberculosis, sarcoid-
*From the Divisions of Pulmonary, Critical Care, and Sleep Medi- osis, bronchiectasis, bronchial cysts and bullae, ankylos-
cine (Dr. Soubani) and Infectious Diseases (Dr. Chandrasekar), ing spondylitis, neoplasm, or pulmonary infarction.5,6
Wayne State University School of Medicine, Detroit, MI.
Manuscript received February 27, 2001; revision accepted Of these, tuberculosis is the most frequently associated
August 29, 2001. condition.7 Occasionally, aspergilloma has been de-
Correspondence to: Ayman O. Soubani, MD, Harper University scribed in cavities caused by other fungal infections.8,9
Hospital, Division of Pulmonary, Critical Care, and Sleep Med-
icine, 3990 John R-3 Hudson, Detroit, MI 48201; e-mail: It is believed that inadequate drainage facilitates the
asoubani@intmed.wayne.edu growth of Aspergillus on the walls of these cavities.

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 Figure 1. The clinical spectrum of conditions resulting from the inhalation of Aspergillus spores.
ICH ⫽ immunocompromised host.

Usually, the fungus does not invade the surrounding Diagnosis

lung parenchyma or blood vessels; exceptions, how-
ever, have been noted.2,10 Aspergilloma usually comes to clinical attention as
The natural history of aspergilloma is variable. In an incidental finding on a routine chest radiograph or
the majority of cases, the lesion remains stable, during an evaluation of hemoptysis. Radiologically,
however, in approximately 10% of cases, it may aspergilloma is evident as an upper-lobe, mobile,
decrease in size or resolve spontaneously without intracavitary mass with an air crescent in the periph-
treatment.11 Rarely, the aspergilloma increases in ery.22 The adjacent pleura may be thickened. At
size.12 times, the mass may be difficult to see on a routine
chest radiograph, and tomography or chest CT scan
may be necessary to visualize the aspergilloma 23 (Fig
Clinical Picture 2). A change in the position of the aspergilloma with
An aspergilloma may exist for years without caus- a change of position of the patient is an interesting
ing symptoms. Most patients will experience mild but variable sign.23 The differential diagnosis of this
hemoptysis, but severe hemoptysis may occur, par- radiologic appearance includes hematoma, neo-
ticularly in patients with underlying tuberculosis.13
Bleeding usually occurs from bronchial blood ves-
sels. Theories on the cause of the hemoptysis include
local invasion of blood vessels lining the cavity,
endotoxins released by the fungus with hemolytic
properties, and mechanical friction of the aspergil-
loma with the cavity wall blood vessels.2,14,15 The
mortality rate from hemoptysis ranges between 2%
and 14%.16 –20 Other symptoms include chronic
cough and dyspnea that are probably more related to
the underlying lung disease. Fever is rare unless
there is secondary bacterial infection.
Risk factors associated with poor prognosis of
aspergilloma are severe underlying disease, increas-
ing size or number of lesions as seen on chest
radiographs, immunosuppression (including cortico-
steroid treatment), increasing Aspergillus-specific
Figure 2. Chest CT scan of a patient with a history of lung
IgG titers, recurrent large-volume hemoptysis, and cancer and tuberculosis, who developed aspergilloma after un-
underlying sarcoidosis or HIV infection.21 dergoing resection of the right upper lobe.

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 plasm, abscess, hydatid cyst, and Wegener granulo- Chronic Necrotizing Aspergillosis
matosis. It is important to note that aspergilloma may
coexist with any of the above conditions.24,25 Also called semi-invasive aspergillosis, this entity
was first described in two reports in 1981 and
A sputum examination may reveal the presence of
1982.40,41 Chronic necrotizing aspergillosis (CNA) is
Aspergillus but is negative in 50% of the cases.26
an indolent, destructive process of the lung due to
Serum IgG antibodies to Aspergillus are positive in
invasion by Aspergillus species (usually A fumigatus).
almost all cases; however, they may be falsely nega- This entity is different from aspergilloma in that
tive in the rare cases of aspergilloma due to species there is local invasion of the lung tissue, and a
other than A fumigatus or in patients receiving preexisting cavity is not needed, although a cavity
corticosteroid therapy.10 Immediate skin reactivity is with a fungal ball may develop in the lung as a
much less helpful in the evaluation of aspergilloma secondary phenomenon due to destruction by the
and is positive only in a minority of patients.26 fungus. On occasion, an aspergilloma may invade the
cavity wall, causing local parenchyma destruction, as
Treatment seen in patients with CNA.42 CNA is also different
from invasive aspergillosis. The former, in contrast to
In asymptomatic patients, no therapy is warranted. the latter, is a chronic process that progresses slowly
There is no consistent evidence that aspergilloma over months to years, and there is no vascular
responds to antifungal agents, and these drugs rarely invasion or dissemination to other organs.40
achieve the minimal inhibitory concentrations within CNA is usually seen in middle-aged and elderly
the lung cavities.27 Inhaled, intracavitary, and endo- patients with documented or suspected underlying
bronchial instillations of antifungal agents have been lung diseases like COPD, inactive tuberculosis, pre-
tried with no consistent success.19,28,29 In addition, vious lung resection, radiation therapy, pneumoco-
systemic antifungal therapy using IV amphotericin B niosis, cystic fibrosis, lung infarction, or, rarely,
failed to show a benefit in patients with aspergil- sarcoidosis.43 It also has been described in patients
loma.30 Itraconazole therapy has been tried with with mild immunosuppression, including those with
variable results.31–33 Bronchial artery embolization diabetes mellitus, those with poor nutrition, those
rarely results in control of hemoptysis because of the undergoing low-dose corticosteroid therapy, and
massive collateral blood vessels; however, this pro- those with connective tissue diseases such as rheu-
cedure should be considered as a temporizing mea- matoid arthritis and ankylosing spondylitis.40
sure in patients with life-threatening hemoptysis.34 The patient usually presents with fever, cough,
The surgical treatment of aspergilloma is associated sputum production, and weight loss of 1 to 6 months’
with relatively high mortality rate that ranges be- duration. A minority of the patients may be asymp-
tween 7% and 23%.15–17,35–38 The most common tomatic.40 The chest radiograph usually shows an
causes of death following surgery are severe under- infiltrative process in the upper lobes or the superior
lying lung disease, pneumonia, acute myocardial segments of the lower lobes. A fungal ball may be
infarction, and IPA.19,38 In addition, there is signifi- seen in nearly one half of the cases.40 Adjacent
cant postoperative morbidity, including bleeding, pleural thickening is a characteristic finding and may
residual pleural space, bronchopulmonary fistula, be an early indication of a locally invasive process.41
empyema, and respiratory failure. A recent report39 The diagnosis is confirmed by a histologic demon-
of 87 patients who were operated on for pulmonary stration of tissue invasion by the fungus and the
aspergilloma revealed a postoperative mortality rate growth of Aspergillus species on a culture. However,
of 5.7%. Another report38 showed a lower mortality the yield of transbronchial biopsy specimens or
rate of 1.5% and morbidity of 18% in the surgical percutaneous aspirates is relatively poor, and a tho-
treatment of aspergilloma; however, most of the racoscopic or open-lung biopsy is rarely performed
patients were young with adequate respiratory re- in these patients. So, a clinical diagnosis of CNA
serve, and tuberculosis was the underlying lung could be made using the following criteria:
disease in the vast majority of the patients. • Clinical and radiologic features consistent with the
In summary, observation alone is adequate in most diagnosis;
cases of aspergilloma. Medical therapy with bed rest, • Isolation of Aspergillus species by culture from
humidified oxygen, cough suppressants, and postural sputum or from bronchoscopic or percutaneous
drainage is helpful in cases of mild hemoptysis. The samples; and
surgical approach needs to be considered in patients • Exclusion of other conditions with similar presen-
with massive hemoptysis and adequate pulmonary tations, such as active tuberculosis, atypical myco-
reserves.20 The role of itraconazole is yet to be bacterial infection, chronic cavitary histoplasmosis,
determined. or coccidioidomycosis.

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 Other helpful but nondiagnostic tests include bone marrow transplantation (BMT), is another in-
serum IgG antibodies to Aspergillus (positive results creasingly significant risk factor for IPA.52 It is
in ⬎ 90% of the patients) and immediate skin reac- estimated that 5% of BMT recipients develop IPA
tivity for Aspergillus antigens. with mortality rates ranging between 30% and
Treatment with antifungal medications is indi- 80%.53–55 In BMT recipients, IPA may be seen in the
cated once the diagnosis is made. The response to first few weeks after the procedure with delayed
therapy with IV amphotericin B is generally favor- engraftment or graft failure, and more commonly in
able.40,42 However, therapy with itraconazole has the setting of treatment with corticosteroids for
emerged as an effective alternative to the relatively graft-vs-host disease. The increased risk of IPA in
toxic amphotericin B.42,44 Surgical resection is gen- patients undergoing transplantation is related to
erally reserved for healthy young patients with focal multiple immune defects including prolonged neu-
disease and good pulmonary reserves, patients not tropenia in the pre-engraftment phase of BMT, and
tolerating antifungal therapy, and patients with re- the use of multiple antirejection or anti-graft-vs-host
sidual localized but active disease despite adequate disease therapy, including corticosteroids and cyclo-
antifungal treatment. In the initial series by Binder sporine. In addition, other factors that predispose
et al,40 90% of patients who underwent surgical patients to fungal infections in general, such as
resections had good responses. However, there were parenteral nutrition, use of multiple antibiotics, and
significant postoperative complications, and one pa- prolonged hospitalization, increase the risk of IPA
tient died.40 following transplantation. IPA also has been re-
The long-term prognosis for patients with CNA is ported increasingly in patients with HIV infection.51
not well-documented. In the original series,40 73% of While most HIV-infected patients have the same risk
the patients were alive 1 to 2 years following therapy, factors for Aspergillus infection as those in other
and the majority of deaths was due to other causes. patient populations (such as patients with neutrope-
nia and those receiving corticosteroid therapy), there
are a growing number of reports of IPA in AIDS
IPA patients without the traditional risk factors.56,57 Be-
sides the usual clinical picture of IPA, there is
The incidence of IPA has been on the rise since it increased incidence of tracheobronchial involve-
was first described in 1953.45 Groll et al46 docu- ment.58 The response to therapy is particularly poor
mented a rise in the rate of invasive mycoses from in the HIV-infected population.51
0.4 to 3.1% of all autopsies performed between 1978 Rarely, IPA has been reported59,60 in apparently
and 1992. In addition, invasive aspergillosis in- immunocompetent patients or in those individuals
creased from 17% of all mycoses found on autopsy at who are mildly immunocompromised, such as pa-
the beginning of the study to 60% at the end of the tients with alcoholism, chronic liver disease, or dia-
14-year study period. betic ketoacidosis. In addition, IPA is increasingly
The vast majority of IPA cases are seen in immu- recognized in patients with advanced COPD, espe-
nocompromised patients. The risk factors are sum- cially those treated with oral corticosteroids.61,62 In a
marized in Table 1.47–51 Neutropenia is the most recent review63 of 545 patients with invasive as-
important risk factor, and it is estimated that IPA pergillosis, BMT was the most frequent risk factor
accounts for 7.5% of all infections in neutropenic (32%; autologous BMT, 7%; allogeneic BMT, 25%),
patients following induction therapy for acute my- followed by hematologic malignancy (29%), solid
elogenous leukemia.47 The risk of IPA increases with organ transplantation (9%), and AIDS (8%). In 2% of
the duration of neutropenia (ie, neutrophil count, patients, no underlying risk factors were identified.
⬍ 500 cells/␮L) and is estimated to be 1% per day
for the first 3 weeks, after which time it increases to
4% per day.47 Transplantation, especially lung and Clinical Picture
The lower respiratory tract is almost always the
primary focus of infection as a result of the inhalation
Table 1—Major Risk Factors for IPA of the infectious spores. Less commonly, IPA may
start in locations other than the lungs, like the
1. Prolonged neutropenia (⬎ 3 wk) or neutrophil dysfunction
(chronic granulomatous disease)
sinuses, the GI tract, or the skin (ie, resulting from
2. Corticosteroid therapy (especially prolonged, high-dose therapy) the insertion of IV catheters, prolonged skin contact
3. Transplantation (highest risk is with lung and bone marrow) with adhesive tapes, or burns).64 – 67
4. Hematologic malignancy (risk is higher with leukemia) Consequently, patients usually present with respi-
5. Cytotoxic therapy ratory symptoms that are consistent with broncho-
6. AIDS (risk increases with lower CD4 count)
pneumonia, with fever, cough, sputum production,

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 and dyspnea. Two other symptoms that are signifi- include rounded densities, pleural-based infiltrates
cant and that raise the possibility of IPA in the that are suggestive of pulmonary infarctions, and
appropriate clinical setting are pleuritic chest pain cavitation. Pleural effusions are uncommon.77,78 The
(due to small pulmonary infarctions secondary to chest CT scan, especially with high-resolution im-
vascular invasion) and hemoptysis that is usually mild ages, is a much more helpful tool in the diagnosis of
but could be massive. IPA is one of the most IPA. It leads to earlier diagnosis, and aids further
common causes of hemoptysis in neutropenic pa- diagnostic studies like bronchoscopy and open-lung
tients; and has been reported to be associated with biopsy.79,80 The routine use of high-resolution chest
cavitation that occurs with neutrophil recovery.68 CT scans in patients with suspected IPA has been
Other pulmonary manifestations include isolated associated with better outcomes, probably due to
tracheobronchitis with severe inflammation of the earlier diagnosis. Of the 156 patients who underwent
airways that is associated with ulcerations and plaque chest CT scans in the report by Patterson et al,63
formation. This may lead to airway obstruction and 85% had findings that were suggestive of IPA.
secondary atelectasis. This form of IPA has been Typical chest CT scan findings are multiple nodules
most commonly reported in patients with AIDS and (Fig 3), the halo sign, which is an early radiologic
in lung transplant recipients 69,70 sign that appears as a zone of low attenuation due to
With the predilection of Aspergillus to invade hemorrhage surrounding the pulmonary nodule,81
blood vessels, IPA commonly leads to areas of and the air crescent sign, which is a crescent-shaped
infarction and hemorrhage in the primary organ lucency in the region of the original nodule second-
(usually the lungs), and the organism spreads hema- ary to necrosis.82 The air crescent sign usually cor-
togenously to other organs, most commonly the relates with recovery from neutropenia and is a
brain (leading to seizures, ring-enhancing lesions, relatively late sign.83 The last two radiologic signs are
cerebral infarctions, intracranial hemorrhage, men- relatively specific for IPA, but they are neither
ingitis, and epidural abscess), and less commonly sensitive nor pathognomonic; other infections like
skin, kidneys, pleura, heart, esophagus, liver, or any nocardiosis and zygomycoses may have a similar
other site.71 appearance.81,82
BAL is helpful in the diagnosis of IPA, especially
in patients with diffuse lung involvement. The BAL
Diagnosis
fluid is tested by fungal smear and culture. The
The diagnosis of IPA is difficult. A high index of specificity of a positive result of BAL fluid testing is
suspicion is necessary in patients with risk factors for very high, reaching 97%,84 but the sensitivity is
invasive aspergillosis. The diagnosis is best made by reported to be approximately 30 to 50%.84,85 Trans-
demonstrating the presence of septate, acute, bronchial biopsies have not been shown to add much
branching hyphae in the lung tissue sample along to the results of BAL and are associated with in-
with a culture that is positive for Aspergillus from the creased risks.19 Open or thoracoscopic lung biopsies
same site. Methenamine-silver and periodic acid- are generally the “gold standard” in the diagnosis of
Schiff stains are the usual stains to demonstrate the
characteristic hyphae. Other fungi such as Fusarium
and Scedosporium may have similar appearances,
thus increasing the importance of performing a
culture for the accurate identification of the fungus.
The presence of the Aspergillus species in sputum
samples could be due to colonization of the airway;
however, in the immunocompromised patient spu-
tum culture positivity may be the only indication of
IPA. Studies72–74 have shown that sputum samples
that are positive for Aspergillus in patients with
leukemia or in those who have undergone BMT have
a positive predictive value of 80 to 90%. On the other
hand, a sputum sample that is negative for Aspergil-
lus does not exclude the diagnosis of IPA, since
negative sputum studies have been noted in 70% of
patients with confirmed IPA.75 Blood cultures rarely
have positive results.76
Figure 3. Chest CT scan of a patient with chronic lymphocytic
The chest radiograph often shows nonspecific leukemia and histologically proven IPA showing multiple pulmo-
changes. The lesions that are suggestive of IPA nary nodules.

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 pulmonary problems in immunocompromised pa- Treatment
tients; however, in the case of IPA, this procedure is
The treatment of IPA is difficult, and the mortality
known to be associated with false-negative results. In
rate remains high despite recent advances in ther-
a study86 of 15 patients who had undergone open-
apy. Empiric therapy should be started as soon as
lung biopsies, the presence of IPA was missed in 3.
there is clinical suspicion of IPA, and while a workup
Thus, open-lung biopsy is reserved for patients in
is underway. The outcome of therapy is dependent
whom the diagnosis of IPA remains uncertain de-
on an early diagnosis, the absence of dissemination,
spite results from the mentioned studies, and when
the instigation of intensive antifungal therapy, and
such a procedure is expected to have an impact on
the recovery of the underlying host defense defect,
the patients’ management and outcome.
such as the resolution of neutropenia or the tapering
Serology has not been useful in the diagnosis of
of immunosuppression therapy.96 –98 In the review by
IPA. Aspergillus antibody detection is not useful,
Patterson et al,63 patients who had severe immuno-
probably due to the poor immune response of
suppression, such as those who had undergone BMT
patients with IPA and the rapidity with which the
and had hematologic malignancy, had poor re-
infection occurs, not giving enough time for an sponses to therapy compared to less severely immu-
adequate antibody response.87 nosuppressed patients (28% vs 51%, respectively).
There has been increasing interest in Aspergillus Also, when IPA was limited to the lung, the response
antigen detection from serum and BAL samples. was better than in patients with disseminated infec-
Some studies88 suggest that antigenemia may be tion (40% vs 18%, respectively). The most widely
detected before the presence of clinical features of used drug in the treatment of IPA is amphotericin B.
IPA. A sandwich enzyme-linked immunosorbent as- Its usual dose is 0.6 to 1.2 mg/kg/d; however, higher
say technique that utilizes monoclonal antibodies to doses (ie, 1 to 1.5 mg/kg/d) may be necessary in
galactomannan (ie, the cell wall glycoprotein that severely immunocompromised patients with over-
binds lectin) has been developed to detect the whelming infections.99 The optimal duration of an-
Aspergillus antigen in serum, urine, and BAL fluid tifungal drug therapy is not known, but treatment is
and has a reported sensitivity and specificity of recommended to continue past the period of immu-
⬎ 90%.88 –92 This method, while commercially avail- nosuppression and until the disease appears to be
able in Western Europe, has not yet been approved clinically resolved.19 Even with optimal therapy, the
in the United States. response rate varies widely between 20% and
Polymerase chain reaction is another experimental 83%.100
method with which to diagnose IPA by the detection Amphotericin B is known to cause serious side
of Aspergillus DNA in BAL fluid and serum. The effects such as nephrotoxicity, electrolyte distur-
extrasensitive nature of this method and the ubiqui- bances, and hypersensitivity reactions. Newer lipid-
tous presence of the fungus create a high likelihood based preparations of amphotericin B (eg, liposomal
of false-positive results.93,94 amphotericin B and lipid complex amphotericin B)
have been introduced in an effort to minimize these
The National Institute of Immunology, Allergy,
side effects. These preparations enable the adminis-
and Infectious Diseases has provided a working
tration of higher doses of amphotericin B with less
case definition. The diagnosis of IPA is definite
toxicity and are indicated in patients who are at high
when tissue histopathology shows the hyphae, with risk for nephrotoxicity, who develop toxicity while
or without a positive culture for Aspergillus from receiving amphotericin B, or who respond poorly to
the same site, or a positive culture from tissue that medication.19,101–104
obtained by an invasive procedure such as trans- Itraconazole, a triazole, is another agent that is
bronchial biopsy, percutaneous needle aspiration, used in the treatment of IPA, in doses of 200 to 400
or open-lung biopsy. The diagnosis of IPA is mg/d.30,105 The drug is available in oral (ie, capsule
probable when the clinical picture is consistent and suspension) and IV formulations. The itracon-
with the diagnosis, and when two sputum cul- azole capsule should be avoided in the treatment of
tures or one BAL fluid culture, a bronchial wash- IPA in view of its poor bioavailability. In a large
ing culture, or a brushing culture for Aspergillus nonrandomized study,95 itraconazole was found to
species, or a cytologic examination of the BAL result in complete or partial response in 39% of
fluid shows the characteristic hyphae or positive patients with IPA, and in a failure to respond to
Aspergillus antigen in the serum or BAL fluid. The treatment in 26%. The results were particularly poor
diagnosis is possible when the clinical picture is in allogeneic BMT recipients and AIDS patients. It
compatible without documentation of any myco- is reasonable to consider therapy with itraconazole as
logic evidence of IPA.63,95 an alterative to that with amphotericin B in patients

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 with IPA who are less immunocompromised and in ABPA.116,117 The factors leading to ABPA are not
the late stages of therapy after the initial control of clearly understood. It is believed that Aspergillus-
the infection with amphotericin B therapy. Because specific, IgE-mediated type I hypersensitivity reac-
of drug-drug interactions, itraconazole needs to be tions and specific IgG-mediated type III hypersen-
used with caution. The use of combination therapy sitivity reactions play a central role in the
(for example, amphotericin B with 5-fluorocytosine, pathogenesis of ABPA.118,119 Other host factors,
rifampin, itraconazole, or ketoconazole) has not been including cellular immunity, may contribute to the
shown to be more effective in the treatment of pathologic changes seen in ABPA.120,121 Since the
patients with IPA.106 Trials19 are currently underway diagnosis of ABPA is usually made on clinical
testing several new promising drugs like voricon- grounds, lung biopsies are rarely performed. In a
azole, posaconazole, and echinocandin derivatives. study122 of 18 pathologic specimens from patients
Caspofungin, an echinocandin derivative was re- with ABPA, the most significant findings involved
cently approved107 for the treatment of IPA in the bronchi and bronchioles with bronchocentric
patients with refractory infection or those intolerant granulomas in 15 specimens and mucoid impaction
to conventional therapy. in 11. Other findings included granulomatous in-
Other modalities of therapy include surgical resec- flammation with histiocytes and lymphocytes, in-
tion, which should be considered in cases of massive creased numbers of eosinophils, and exudative bron-
hemoptysis,108 or the resection of residual localized chiolitis. Fungal hyphae were commonly seen
pulmonary lesions in patients with continuing immu- without evidence of tissue invasion.122
nosuppression or those who are expected to have
further immunosuppressive therapy in the future.109
Diagnosis
Surgery has been performed safely in selected neu-
tropenic patients.109 –111 The surgical outcome is ABPA is usually suspected on clinical grounds, and
poor in patients with multiple foci of infection, in the diagnosis is confirmed by radiologic and sero-
those who have undergone allogeneic BMT, and logic testing. The patient usually presents with
those requiring mechanical ventilation. wheezing, expectoration of brown mucus plugs,
The value of immunomodulatory therapy such as pleuritic chest pain, and fever.123 The chest radio-
that using cytokines (ie, granulocyte colony-stimulat- graph findings may be normal in the early stages of
ing factor, granulocyte macrophage-colony-stimulat- the disease. During acute exacerbations, the typical
ing factor, or interferon-␥) as adjuvant therapy is not findings are fleeting pulmonary infiltrates that tend
clear, and large studies on the safety and efficacy of to be in the upper lobe and central in location. There
these agents are lacking.112 may be loss of volume due to mucoid impaction of
Given the difficulties in the management of IPA, the airways. This latter manifestation may present as
an important approach to this problem is prophylaxis band-like opacities emanating from the hilum with
for those patients who are at increased risk for IPA. rounded distal margins (gloved finger appear-
Avoiding the hospitalization of patients in areas ance).124 At later stages, central bronchiectasis and
where there is construction and the use of high- pulmonary fibrosis develop. The chest CT scan is
efficiency particulate air or laminar air flow have more sensitive in demonstrating the above changes.
been shown to decrease the rate of IPA in some The IgE level serves as a marker for flare-ups and
studies.113 Also chemoprophylaxis using low-dose responses to therapy.125 A positive sputum culture
amphotericin B and intranasal amphotericin B have for A fumigatus is not essential for the diagnosis, and
been studied with variable results.114,115 Currently indeed in rare cases a syndrome similar to ABPA is
chemoprophylaxis trials using itraconazole and triggered by fungi other than Aspergillus. Immediate
posaconazole are underway in allogeneic BMT re- skin reactivity to A fumigatus antigens and elevated
cipients. levels of serum IgG antibodies to Aspergillus are
usually present.118 Lung biopsy is rarely performed
for the diagnosis of ABPA.
Allergic Bronchopulmonary Aspergillosis Greenberger and Patterson recently modified the
diagnostic criteria for ABPA (Table 2).123,125 Not all
Allergic bronchopulmonary aspergillosis (ABPA) is of these criteria need to be present to diagnose
a hypersensitivity reaction to Aspergillus antigens, ABPA. Withholding therapy until the development
mostly due to A fumigatus. It is typically seen in of all clinical symptoms and evidence of bronchiec-
patients with long-standing asthma or cystic fibrosis, tasis may lead to a missed diagnosis in a significant
and it is estimated that 7 to 14% of corticosteroid- number of patients and to delayed treatment result-
dependent asthma patients and 6% of patients with ing in irreversible pulmonary damage. Therefore,
cystic fibrosis meet the diagnostic criteria for ABPA may be subdivided into the following two

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 Table 2—Diagnostic Criteria for ABPA Aspergillus antigens and the secondary inflammatory
reaction. Treatment with corticosteroids leads to the
1. Asthma
2. Immediate skin reactivity to Aspergillus relief of bronchospasm, the clearing of pulmonary
3. Serum precipitins to A fumigatus infiltrates, and a decrease in IgE level and peripheral
4. Increased serum IgE and IgG to A fumigatus eosinophilia.130,131 Oral prednisone is administered
5. Total serum IgE ⬎ 1,000 ng/mL at 0.5 mg/kg/d for 2 weeks then gradually is ta-
6. Current or previous pulmonary infiltrates
pered.132 The duration of therapy should be individ-
7. Central bronchiectasis
8. Peripheral eosinophilia (1,000 cells/␮L) ualized according to the patient’s clinical condition.
Most patients, however, require prolonged low-dose
corticosteroid therapy to control their symptoms and
groups: patients with or without central bronchiec- minimize relapses.132,133 Inhaled steroids are not
tasis. The essential criteria for diagnosis of the group helpful in preventing the progression of lung damage
with ABPA and central bronchiectasis are asthma, associated with ABPA.134
immediate skin reactivity to Aspergillus antigens, Since there are side effects associated with long-
serum IgE level ⬎ 1,000 ng/mL, and central bron- term corticosteroid therapy, including an increased
chiectasis. Patients without central bronchiectasis risk of invasive aspergillosis,135 interest in other
are labeled ABPA-seropositive, and the minimal modalities of treatment of ABPA has developed.
criteria for diagnosis are asthma, immediate skin Recently, a randomized prospective study136 was
reactivity to Aspergillus, serum IgE level ⬎ 1,000 performed to evaluate the role of an antifungal
ng/mL, history of pulmonary infiltrates, and elevated agent, itraconazole, in the management of ABPA.
levels of serum IgE and IgG antibodies to A fumiga- The study showed that 46% of patients treated with
tus.127 itraconazole, 200 mg bid for 16 weeks, had a signif-
Patterson et al128 divided this syndrome into five icant response, which was defined as a 50% reduc-
stages that help to guide the management of the tion in the corticosteroid dose, a decrease of at least
disease. It is not necessary for a patient to progress 25% in the serum IgE concentration, and a 25%
through all of these stages. Stage 1 (acute stage) is improvement in exercise tolerance or pulmonary
characterized by asthma, a markedly elevated IgE function test results, or the resolution or absence of
level, peripheral eosinophilia, pulmonary infiltrates, pulmonary infiltrates. There was no significant tox-
and the presence of IgE and IgG antibodies to icity related to this therapy. The study concluded
A fumigatus. In practice, patients are rarely identi- that patients with ABPA generally benefit from
fied in this stage. In stage II (remission stage), the concurrent itraconazole therapy and suggested that a
IgE level falls, but not to the normal range, eosino- lower dose of itraconazole (200 mg daily) was equally
philia is absent, and the chest radiograph is clear. beneficial and may be useful as a maintenance
Serum IgG antibodies to Aspergillus may be slightly therapy to sustain remission.
elevated. Stage III (exacerbation stage) is diagnosed
in a patient who is known to have ABPA and is
Syndromes Related to ABPA
similar to stage I. The IgE level is usually double that
at baseline. Stage IV (the corticosteroid-dependent Mucoid Impaction: This feature of ABPA may be
stage) occurs when the patient becomes steroid- seen without asthma or other features of the disease.
dependent and attempts to taper the steroid therapy, The patient usually presents with a cough and ex-
resulting in an obvious worsening of symptoms and pectoration of mucus plugs.137 The mucus plugging
the development of pulmonary infiltrates. The serum may lead to atelectasis, which may arouse suspicion
IgE level is usually elevated but may be normal. of endobronchial malignancy.138
Frequently, the chest CT scan will show central
bronchiectasis. Unfortunately, the syndrome is diag- Bronchocentric Granulomatosis: This syndrome is
nosed in the majority of patients at this stage.129 characterized by necrotizing granulomas that ob-
Stage V (fibrotic stage) is characterized by clinical struct and destroy the bronchioles. The Aspergillus
features of end-stage lung disease with dyspnea, hyphae are identified within the granulomas in 40 to
cyanosis, rales, and cor pulmonale. Clubbing may be 50% of patients with bronchocentric granulomato-
present. The serum IgE level and eosinophil count sis.99 The lung parenchyma is marked by the pres-
may be low or high. A minority of patients progress ence eosinophilic inflammatory infiltrates and fibro-
to this stage. sis, however, there is no tissue or vascular invasion by
the Aspergillus. Clinically, the patients are almost
Treatment
always asthmatic and have a persistent cough with
The mainstay of therapy for ABPA is oral cortico- peripheral eosinophilia and increased serum IgE
steroids to suppress the immunologic response to levels. The chest radiograph usually shows solitary or

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