Allergic Bronchopulmonary Aspergillosis
Karen Patterson1 and Mary E. Strek1
1
Department of Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, Illinois
Allergic bronchopulmonary aspergillosis (ABPA) is a complex clinical
entity that results from an allergic immune response to Aspergillus
fumigatus, most often occurring in a patient with asthma or cystic
fibrosis. Sensitization to aspergillus in the allergic host leads to
activation of T helper 2 lymphocytes, which play a key role in
recruiting eosinophils and other inflammatory mediators. ABPA is
defined by a constellation of clinical, laboratory, and radiographic
criteria that include active asthma, serum eosinophilia, an elevated
total IgE level, fleeting pulmonary parenchymal opacities, bronchi-
ectasis, and evidence for sensitization to Aspergillus fumigatus by
skin testing. Specific diagnostic criteria exist and have evolved over
the past several decades. Staging can be helpful to distinguish
active disease from remission or end-stage bronchiectasis with
progressive destruction of lung parenchyma and loss of lung
function. Early recognition allows treatment with corticosteroids,
which are effective but may be required indefinitely. There is some
evidence to support the use of newer antifungal azoles as cortico-
steroid-sparing agents. Patients must be followed closely for re-
current disease. ABPA should be considered in all patients with
asthma or cystic fibrosis, but especially in those with difficult to
control disease.
Keywords: allergic bronchopulmonary aspergillosis; ABPA; asthma;
cystic fibrosis; aspergillus
Allergic bronchopulmonary aspergillosis (ABPA) is an indolent
and potentially progressive disease resulting from a hypersensi-
tivity response to persistent Aspergillus fumagatus in the airways.
Advances have been made in our understanding of the role of
the allergic response in the pathophysiology of this disease (1, 2).
ABPA occurs most commonly in patients with asthma or cystic
fibrosis (CF), especially those with coexisting atopy (3, 4).
Patients present with symptoms that may be attributed to their
underlying disease; therefore, considering ABPA in these patient
populations is important. Therapy is directed at mitigating the
allergic inflammatory response (5). Early diagnosis and treatment
has been thought to prevent disease progression, parenchymal
damage, and loss of lung function. In this review we highlight
salient clinical features and the current understanding of the
pathophysiology of ABPA and review treatment options.
BACKGROUND AND EPIDEMIOLOGY
Aspergillus is a fungus that is found throughout the world. Its
spores are hardy and ubiquitous, thriving in moist, organic
materials. Aspergillus can be cultured from outdoor and indoor
environments and grows optimally at core body temperature
(1). Spores are tiny and easily aerosolized and deposit in distal
and terminal airways, where they germinate if the airway
environment is favorable. Aspergillus is variably pathogenic in
humans. Host characteristics are a major determinant of the
(Received in original form August 10, 2009; accepted in final form September 8, 2009)
Correspondence and requests for reprints should be addressed to Mary E. Strek,
M.D., The University of Chicago, Department of Medicine – MC7076, Chicago,
IL 60637. E-mail: mstrek@medicine.bsd.uchicago.edu
Proc Am Thorac Soc Vol 7. pp 237–244, 2010
DOI: 10.1513/pats.200908-086AL
Internet address: www.atsjournals.org
type of pulmonary disease that may develop in response to
aspergillus exposure (6) (Table 1). ABPA, one of the many
forms of aspergillus disease, results from a hyperreactive im-
mune response to A. fumigatus without tissue invasion.
ABPA occurs almost exclusively in patients with asthma or
CF who have concomitant atopy. The precise incidence of
ABPA in patients with asthma and CF is not known but it is
not high. Approximately 2% of patients with asthma and 1 to
15% of patients with CF develop ABPA (2, 4). Although the
incidence of ABPA has been shown to increase in some areas of
the world during months when total mold counts are high,
ABPA occurs year round, and the incidence has not been
definitively shown to correlate with total ambient aspergillus
spore counts (1, 7). There is no gender predilection noted.
PATHOPHYSIOLOGY
The pathophysiology of ABPA is complex. In an allergic host,
the persistence of A. fumigatus in the lung leads to T lympho-
cyte activation, cytokine, and immunoglobulin (Ig) release and
inflammatory cell recruitment. Local inflammation results in
mucus production, airway hyperreactivity, and ultimately bron-
chiectasis.
A viscous mucus layer in the airway, combined with dys-
functional clearance in the case of CF, may disrupt the natural
process of effective spore removal (2, 8). Aspergillus proteolytic
products may also interfere with airway clearance by damage to
and disruption of the epithelial cell barrier (4, 9). Once resident,
aspergillus germinates and proliferates, and antigen burdens can
become high. Dendritic cells are local antigen-presenting cells
that process spore and mycelia antigens. This processing leads
to the release of specific cytokines by antigen-presenting cells
and to antigen presentation to T lymphocytes (10). In the
normal host, the response to antigen presentation is activation
of nonallergic T helper (Th)1 and allergic (Th2) lymphocytes
(10, 11). The Th1 response is marked by macrophage and
neutrophil cytotoxic action as well as IgG and IgA antibody
production, which may protect against aspergillus infection (12).
A frank defect in the Th1 cytotoxic pathway is not present in
ABPA, although it is present in immunocompromised patients
who are at risk for invasive disease. Activation of the Th2
pathway results in specific cytokine and immunoglobulin elab-
oration that mediate allergic inflammation. Th2 signaling pre-
dominates in the aspergillus allergic host; the imbalance of the
Th2 over the Th1 response is thought to drive ABPA (1, 4).
Although the Th2 response predominates in patients with
allergy to aspergillus and in patients with ABPA, the magnitude
of the Th2 immune activation is greatest in ABPA (12).
Activated Th2 cells release specific cytokines that orches-
trate downstream cell signaling and the inflammatory response
(11). IL-4 may be especially important. It is linked to B-cell
isotype conversion to IgE production, the expression of vascular
cell adhesion molecules on endothelial cells and vascular cell
adhesion molecule ligands on eosinophils, and to IgE and IgA
Fc receptor expression on eosinophils (7, 12). When bound to
aspergillus antigen, locally produced IgE may activate mast
cells. Mast cell chemokines, in concert with IL-5, recruit
eosinophils. Eosinophils are the most conspicuous immune cells
238
TABLE 1. PULMONARY MANIFESTATIONS OF ASPERGILLUS
Disease Host
Aspergilloma Cavity from sarcoid, previous TB,
bullae, or bronchiectasis
Allergic bronchopulmonary Asthma, cystic fibrosis
aspergillosis
Chronic necrotizing COPD, previous TB, corticosteroids, DM
aspergillosis
Invasive aspergillosis Immunocompromised, especially
neutropenia
Hypersensitivity pneumonia Intense or repeated exposure to
aspergillus
Definition of abbreviations: COPD 5 chronic obstructive pulmonary disease;
DM 5 diabetes mellitus; TB 5 tuberculosis.
in airway mucosa in patients with ABPA and are thought to be
a major effector of inflammation (12, 13). Degranulation of
activated mast cells and eosinophils results in the release of
mediators of vasodilation and bronchoconstriction (12).
Activated T and B lymphocytes infiltrate lymphatics and
release cytokines systemically. Circulating IL-4 is thought to
drive total IgE production, and total serum IgE levels are
increased out of proportion to aspergillus-specific IgE levels (7).
IgE and IgG antibodies specific for aspergillus circulate system-
ically as well (14).
HOST CHARACTERISTICS
Susceptibility to ABPA is likely mediated by genetically de-
termined inflammatory responses in atopic patients. Although
atopy is an inheritable trait, familial occurrence of ABPA,
though reported, is rare (15). ABPA occurs most commonly in
patients with asthma and CF, two conditions strongly associated
with atopy. Patients with ABPA also are noted to have higher
rates of other atopic conditions, including allergic rhinitis and
conjunctivitis, atopic dermatitis, and food hypersensitivity (16).
Allergic fungal sinusitis results from an allergic response to
aspergillus. Initially thought not to be related, allergic fungal
sinusitis and ABPA share a history of atopy and asthma, and
several reports document an association of these diseases (17,
18). The pathophysiology of allergic fungal sinusitis may involve
abnormal sinus anatomy, which could explain why only a small
fraction of patients with ABPA have concomitant allergic
fungal sinusitis. In addition to atopic conditions, ABPA has
been associated with chronic obstructive pulmonary disease,
previous tuberculosis infection, and treatment of sarcoid with
infliximab (19–21). ABPA has also been reported in hyper-IgE
syndrome, bronchocentric granulomatosis, and chronic granu-
lomatosis disease (6, 17).
ABPA in Asthma
The relationship between asthma and ABPA is incompletely
understood. It is unclear whether having asthma directly increases
the risk for ABPA or whether asthma and ABPA share a common
predisposition. As many as 25% of subjects with asthma are
sensitized to aspergillus, yet only a small fraction develop ABPA
(22). In the aspergillus-specific, IgE-mediated immune response,
abnormalities of the airway and changes in mucus production and
properties may contribute to the development of ABPA in patients
with asthma. CFTR gene mutations are higher in patients with
asthma and ABPA who do not have CF (23). The onset of ABPA
typically occurs many years after the diagnosis of asthma is made
but has been reported in new-onset asthma. Unlike other atopic
conditions that are more common in childhood, the incidence of
ABPA is highest in adults (5, 24).
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7 2010
ABPA in CF
Patients with CF are at risk for developing ABPA (4). The
prevalence of ABPA is increased in patients with CF who are
male, are adolescent, have lower lung function, have a history of
wheezing or asthma, or have pseudomonas in the sputum.
Atopy is present in up to 60% of patients with CF (4). The
impaired airway clearance characteristic of CF may contribute
directly to ABPA, although other factors likely play a role as
well (25, 26).
CLINICAL FEATURES
Symptoms
With the development of ABPA, asthma or CF typically
worsens and may manifest with a new or worsening cough or
an increase in sputum production or wheezing. Thick mucus
production is common; mucus can be remarkably tenacious and
resistant to suctioning (27). Patients may cough up well-formed,
tan to brownish-black mucus plugs. Plugs are composed of de-
generating eosinophils, desquamated epithelial cells, and mucin
(28). Hemoptysis may occur secondary to airway inflammation
and bronchiectasis; however, massive hemoptysis from ABPA
alone is not well described in the literature (5, 29). Systemic
symptoms of low-grade fever, malaise, and weight loss are
variably part of the clinical spectrum of ABPA (16). These
symptoms should trigger an evaluation for ABPA in a patient
with asthma or CF.
Laboratory Evaluation
Total serum IgE levels of at least 1,000 IU/ml are a hallmark of
ABPA (2). A. fumigatus–specific IgE levels are also elevated
(30). Laboratory studies may show elevated serum levels of
aspergillus-specific IgG antibodies, precipitins, and eosinophils
(2, 14). Corticosteroids may blunt an allergic response; there-
fore, patients on systemic corticosteroids may not have eosin-
ophilia or a significantly elevated total serum IgE level but may
still have ABPA.
Radiographic Imaging
Chest radiographs that demonstrate fleeting parenchymal opac-
ities or bronchiectasis should trigger a consideration of ABPA.
Infiltrates are usually eosinophilic in nature and responsive to
corticosteroids and may be misdiagnosed as infectious pneu-
monia (31). Opacities may also reflect bronchoceles, mucus
plugging, atelectasis, or lobar collapse. The full extent of
radiographic findings is best appreciated on chest CT imaging
(Figures 1–3). Bronchiectasis, bronchial wall edema, mucus
plugging, atelectasis, lobar collapse, nodules, and fibrosis also
can be seen (32). Pleural changes may occur but are not
common. The presence of central bronchiectasis in multiple
lobes is highly suggestive of, and varicose or cystic changes are
most specific to ABPA (33). Bronchiectasis is sometimes seen in
the peripheral lung fields (34). Although central bronchiectasis
may occur occasionally in patients with asthma who do not have
ABPA, it is less severe and most often limited to one or two
lobes (35).
Mucus plugging can manifest a ‘‘finger in glove’’ appearance
from impacted mucus opacifying an airway and its branches or
as small nodules from impacted bronchioles cut on end (2, 31,
36). Airway mucus can have normal or high attenuation. In
high-attenuation mucus, the concentration of ions such as cal-
cium, iron, and manganese contributes to a Hounsefield density
that can exceed that of surrounding skeletal muscle (33).
Chemical deposition is a gradual process, and high-attenuation
mucus suggests chronicity. In one report, this was found in 19%
Patterson and Strek: Allergic Bronchopulmonary Aspergillosis 239

Figure 1. Chest CT scan image in a patient with allergic bronchopul- Figure 2. Chest CT scan image in a patient with allergic bronchopul-
monary aspergillosis showing nodular and mass-like opacities. monary aspergillosis showing mucus plugging.

of cases of ABPA (37). Although not as common as central
bronchiectasis, high-attenuation mucus is characteristic of
ABPA.
Fibrosis and cavitation of dilated airways are end-stage
findings in ABPA. Peribronchiolar fibrosis is thought to be
a result of persistent inflammation and progressive broncho-
centric granulomas (29, 38). Fibrosis predisposes to cor pulmo-
nale, and enlarged pulmonary arteries and right ventricular
hypertrophy may be evident on chest CT scanning (39).
may also show infiltration of airways by eosinophils and
lymphocytes, goblet cell hyperplasia, bronchocentric granulo-
mas with distal exudative bronchiolitis, mucoid impaction, and
fibrotic changes in end-stage disease (1, 42).
DIAGNOSIS
There is not a single test to diagnose ABPA; nor is there
a universally recognized set of criteria. However, the diagnostic

Pulmonary Function Testing

Airflow obstruction that is at least partially reversible is
a common finding on pulmonary function tests, especially in
mild or early ABPA. Fixed airflow obstruction and reduced
lung volumes due to interstitial changes reflect progressive dis-
ease. The diffusing capacity may be decreased during an
exacerbation and remains low in end-stage ABPA (2, 40).
Pulmonary function test findings are not specific to ABPA
because most patients typically have underlying lung disease. A
more important role for pulmonary function tests is in tracking
disease over time.

Bronchoscopy and Histology

Bronchoscopic evaluation, fungal culture, and histology are not
required to make a diagnosis of ABPA. Bronchoscopy may be
performed in patients with ABPA when the diagnosis is un-
clear. On bronchoalveolar lavage, eosinophil counts and levels
of IgA, IgG, IgM, and IgE are elevated (41). Aspergillus is not
reliably cultured, even in active disease, and the sensitivity of
staining bronchoalveolar lavage washes or sputum samples for
aspergillus is poor (17). Conversely, the recovery of aspergillus
in culture may reflect colonization alone and is not specific for
active disease. Given the lack of sensitivity or specificity of
aspergillus culture, we agree with recent diagnostic algorithms
that do not require culture for diagnosis. Finding aspergillus on Figure 3. Chest CT scan image in a patient with allergic bronchopul-
lung pathology, however, is diagnostically helpful. Lung biopsy monary aspergillosis showing bronchiectasis in the central or proximal
is not necessary for diagnosis but, when performed in ABPA, two thirds of the lung fields.
240 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7 2010

TABLE 2. EVOLUTION OF DIAGNOSTIC APPROACH

1977 Diagnostic 1986 Recognition of 1991 Diagnostic Criteria:
1952 First Case Series (79) Criteria (43) Limited Disease (47) Revised (44)

Clinical features described Asthma ABPA-CB ABPA-CB

Total IgE elevated
Immediate skin test positive
ABPA-S
Serum eosinophilia
Precipitins
Parenchymal infiltrates
Central bronchiectasis
ABPA with central bronchiectasis Asthma
Immediate skin test positive
Total IgE elevated
Clinical and serologic features without central
Specific IgE and IgG elevated
bronchiectasis
Central bronchiectasis
ABPA-S
Asthma
Immediate skin test positive
Total IgE elevated
Specific IgE & IgG elevated
Additional findings
Mucus plugs
Sputum 1 aspergillus
Precipitins
Parenchymal infiltrates
Delayed skin test positive

Definition of abbreviations: ABPA-CB 5 allergic bronchopulmonary aspergillosis–central bronchiectasis; ABPA-S 5 Allergic bronchopulmonary aspergillosis–serological.

criteria articulated by Rosenberg, and later revised by Green-
berger, are widely accepted (27, 43, 44) (Table 2). A simple
approach to diagnosis is limited by the facts that many of the
diagnostic markers are continuously variable, and most are not
highly specific or sensitive. Integration of clinical, radiographic,
and serologic features and clinical judgment is used to make the
diagnosis of ABPA.
When ABPA is suspected, a serum total IgE level and skin
testing for hypersensitivity to A. fumigatus should be performed.
A positive skin test in the form of an immediate IgE-mediated
response is highly sensitive for aspergillus sensitization but not
specific for ABPA (2). IgG-mediated late skin test responses are
variably positive and not usually assessed (16). A wheal di-
ameter of at least 3 mm is required; smaller wheal formation
may occur in patients sensitized to aspergillus or in patients with
non-ABPA aspergillus diseases (16). Intradermally placed skin
tests are more sensitive than the epicutaneous prick test.
If skin testing is positive and total IgE is elevated, A.
fumigatus–specific antibody levels help to distinguish ABPA
from other conditions, such as asthma with aspergillus sensitiv-
ity (1, 2). Historically, precipitin antibodies were useful to make
this distinction in cases of positive skin tests. Precipitins are not
as commonly used for the initial diagnostic evaluation as the
ability to detect aspergillus IgE, and IgG antibody levels are
more easily obtained and are quantitative (27, 29). Although
specific antibody levels are quantifiable, there is a lack of
standardization of laboratory testing to permit precise labora-
tory to laboratory comparison of values (44).
Elevated eosinophil levels were a primary diagnostic feature,
but recent criteria do not incorporate serum eosinophilia (Table
2). Serum eosinophilia is not sensitive or specific but if present
supports a diagnosis of ABPA (45, 46).
Central bronchiectasis is a hallmark finding, although ABPA
without bronchiectasis is also recognized (47). ABPA-S refers
to ABPA diagnosed serologically, whereas ABPA-CB refers to
patients with central bronchiectasis. This distinction does not
correlate well with severity of asthma or degree of serologic
abnormalities (34). Distinguishing between ABPA-S and
ABPA-CB may have prognostic implications: The frequency
of exacerbations and the likelihood of permanent lung damage
are believed to be lower in patients with ABPA-S (48, 49).
ABPA-S may be a more benign phenotype of ABPA, but most
experts consider it a precursor of ABPA-CB.
The diagnosis of ABPA in patients with CF may be particu-
larly challenging (4). Bronchiectasis, thick mucus, and mucus
plugging are often present at baseline in CF. Development of
ABPA is suggested by worsening baseline cough, dyspnea, or
wheeze; increased or colored sputum; the onset of new fevers or
weight loss; or a decline in pulmonary function tests. This should
prompt skin testing and measurement of total serum IgE levels.
Serial CT scanning may be helpful to distinguish infiltrates due to
ABPA over an active infectious process (32) (Table 3). The
diagnostic criteria in CF are reviewed extensively in the CF
Foundation Consensus Conference statement (4). Annual
screening with serum total IgE levels is advised. The degree to
which development of ABPA results in accelerated decline in
lung function in patients with CF requires further study (4, 50).
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for ABPA includes refractory asthma,
newly diagnosed CF, tuberculosis, sarcoidosis, infectious pneu-
monia, eosinophilic pneumonia, aspergillus sensitive asthma,
Churg-Strauss syndrome, and bronchocentric granulomatosis
(2, 24). In addition, fungi other than aspergillus have caused
allergic bronchopulmonary mycosis, a clinical condition identi-
cal to ABPA but with antibody and skin test reflecting allergy to
the implicated mold (51).
NATURAL HISTORY
The clinical course of ABPA is variable. There are five
recognized stages of ABPA, and they are useful to appreciate
the status and trajectory of a given patient (5, 48). Stage I
defines new, active ABPA. Stage II is marked by clinical and
TABLE 3. CLUES TO THE PRESENCE OF ALLERGIC
BRONCHOPULMONARY ASPERGILLOSIS
Asthma Cystic Fibrosis
Mucus production New, brown-black Increased, Brown-Black
Total IgE . 1,000 IU/mL 1 1
Bronchiectasis Central Predominantly central,
extensive
Fleeting pulmonary opacities 1 1
High attenuation mucus plugs 1 1
on chest CT
Patterson and Strek: Allergic Bronchopulmonary Aspergillosis 241

serological remission. Stage III is recurrent active ABPA.
Patients with chronic, steroid-dependent asthma secondary to
ABPA are stage IV. Fibro-cavitary disease secondary to pro-
gressive inflammation and airway dilation defines stage V, which
may lead to progressive respiratory failure and death. ABPA
does not necessarily evolve through these stages in a sequential
manner. At presentation, it is not always clear who will enter
remission, who will have recurrent disease, or who will progress.
Early diagnosis and treatment is thought to be associated with
a lower risk of advanced disease in the future (5, 7, 27, 47).
Changes in serum total IgE level or pulmonary function tests
are useful for objectively assessing remission or recurrence of
ABPA (5, 52). Establishing a patient’s total IgE level during
remission is important to be able to interpret serial values
because levels even in remission are typically above normal (1).
A common approach is to use a sustained decrease of 25 to 35%
to identify remission and an increase of 100% to identify
recurrent disease (2, 27, 52, 53). Changes in total IgE levels
may precede the onset of symptoms or new radiographic
infiltrates, and regular monitoring in high-risk patients can be
useful to screen for the recurrence or development of ABPA.
TREATMENT
The goal of therapy is to induce remission by suppressing the
inflammatory pathway so that further lung destruction does not
occur while minimizing side effects. Remission is defined by
improvement in clinical symptoms, decrease in total serum IgE
level, resolution of radiographic opacities, and improvement in
lung function. A number of medications have been tried in the
treatment of ABPA. These include systemic and inhaled
corticosteroids, antifungal agents, and omalizumab, a monoclo-
nal antibody directed against IgE (2, 27). None of these
medications have been shown to be of benefit in large,
randomized, double-blind, placebo-controlled trials, but there
is considerable support based on case series and expert opinion
for the benefit of oral corticosteroids to induce remission and
prevent progression of disease (Table 4). Corticosteroids de-
crease the inflammatory response to aspergillus in the lung but
at considerable cost in terms of side effects if used chronically.
Corticosteroids do not inhibit the growth of aspergillus. Anti-
fungal agents decrease the antigen burden and subsequent
immune response but cannot be recommended as monotherapy.
The benefit of environmental evaluation and remediation of
ongoing exposure to aspergillus has been debated. Failure to
respond to therapy should prompt consideration of comorbid-
ities such as allergic rhinitis or sinusitis or alternate diagnoses.
Treatment of ABPA in patients with CF is similar, although
higher doses of prednisone are recommended initially (4).
Corticosteroids
Systemic corticosteroids are the mainstay of therapy for ABPA.
They are associated with decreased wheezing, serum total IgE
levels, and eosinophilia, and with resolution of parenchymal
opacities (54, 55). A number of dosing regimens have been
recommended. Some experts think a more aggressive regimen
with higher doses of systemic corticosteroids at disease onset
results in the best long-term outcomes, but the evidence for this
is limited (Table 4). This aggressive regimen involves prednis-
olone 0.75 mg/kg daily for 6 weeks, then 0.5 mg/kg daily for 6
weeks, then tapered by 5 mg daily every 6 weeks, for a total of 6
to 12 months (5, 34). A more conservative approach is to treat
with prednisone 0.5 mg/kg daily for 1 to 2 weeks, then on
alternate days for 6 to 8 weeks, then tapered by 5 to 10 mg daily

TABLE 4. SELECTED STUDIES OF THE TREATMENT OF ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS

Medication Reference Study Description Outcome

Prednisone 0.5 mg/kg
QD 3 1 wk then QOD
Prednisone 0.5 mg/kg
QD 3 2 wk then
QOD 3 3 mo
Prednisolone 0.75 mg/kg
QD 3 6 wk, 0.5 mg/kg
QD 3 6 wk then taper
by 5 mg Q 6 wk
Prednisone 2 mg/kg
QD 3 1 wk then 1 mg/kg
QD 3 1 wk then
QOD and intraconazole
Methylprednisolone IV
15–20 mg/kg
QD 3 3 d Q 4 wk
Budesonide inhaled 400 mg
daily vs. placebo
Nebulized amphotericin B
and budesonide
Itraconazole 200 mg BID vs.
placebo 3 16 wk;
prednisone . 10 mg daily
Itraconazole 400 mg QD vs.
placebo 3 16 wk
Itraconazole/prednisone vs.
intraconazole 200–600 mg
QD
Voriconazole 3 1 yr
Omalizumab
Rosenberg 1977 (43) Case series of 20 patients ‘‘Complete remission’’ in all cases
Patterson 1986 (47) Case series of 84 patients 38 (45%) corticosteroid dependent
Agarwal 2006 (34) Case series of 126 patients 126 ‘‘remission’’ at 6 wk,
25 (20%) ‘‘relapse,’’ 17 (13.5%)
corticosteroid dependent
Nepomuceno 1999 (68) Case series of 16 patients with CF; 1: Decreased wheezing, serum eos,
12 on dual therapy, 2 on radiographic infiltrates, and IgE
prednisone alone 2: Fewer acute episodes
with intraconazole
Thompson 2006 (56) Case series of 4 patients with CF Disease ‘‘control’’ 3 (75%)
Chest 1977 (59) Double-blind trial in 32 patients No benefit asthma score or FEV1
Laoudi 2008 (58) Case series of 3 patients with CF Decreased serum eos, and total and
specific IgE and improved FEV1
Stevens 2000 (66) Randomized double-blind Decreased prednisone dose and total
trial in 55 patients IgE 13/28 (46%), itraconazole vs. 5/27
(19%) placebo
Wark 2003 (67) Randomized double-blind Decreased IgE and fewer exacerbations
trial in 29 patients requiring prednisone with itraconazole
Skov 2002 (69) Retrospective study in patients with Decreased precipitins, increased FEV1
CF (9 both, 12 intraconazole alone) in all; IgE decreased in 56% on
both vs. in 42% on itraconazole
Erwin 2007 (71) Case report, 1 patient Improved symptoms, tapered
prednisone off
Kanu 2008 (75) Case report, 1 patient Improved symptoms and FEV1

Definition of abbreviations: CF 5 cystic fibrosis; Eos 5 eosinophils; Q 5 every; QD 5 daily; QOD 5 every other day.
242
every 2 weeks (27, 54). With either regimen, serum total IgE
concentration is followed closely until clinical and radiographic
remission is achieved. Serum total IgE is repeated every 8 to
12 weeks for 1 year, then annually (5). An increase of greater
than 100% over baseline suggests recurrent disease and may
precede the development of active clinical disease. The chest
roentgenogram or CT scan should be repeated in 4 to 8 weeks to
look for resolution of pulmonary opacities. Pulmonary function
tests are monitored and should improve on therapy. Patients
who cannot be tapered off systemic corticosteroids have evolved
to Stage IV disease and should be managed with alternate-day
corticosteroid therapy if possible and are candidates for anti-
fungal therapy. In a small series, intravenous pulse methylpred-
nisolone was given to children with CF and severe ABPA
because of relapse or intolerance to high-dose oral corticoste-
roids, with disease control achieved in three of the four patients
(56) (Table 4). Patients with CF may have incomplete absorp-
tion of enteric-coated prednisolone (4).
Inhaled corticosteroids have been studied in the treatment of
ABPA (57, 58). A case series of three children with CF and
ABPA showed improvement with nebulized budesonide and
amphotericin B. However, a double-blind, placebo-controlled
study in patients with non-CF ABPA failed to demonstrate the
benefit of beclomethasone 400 mg daily (59).
The side-effects of systemic corticosteroids are numerous
and include weight gain, psychosis, hypertension, hypokalemia,
gastric ulcers, thinning and bruising of skin, osteoporosis, de-
velopment or worsening of diabetes, aseptic joint necrosis,
cataracts, glaucoma, and immune, adrenal, and growth suppres-
sion and in most cases preclude long-term use. Patients treated
with corticosteroids should receive vaccination for pneumococcus
and influenza as well as calcium plus vitamin D with monitoring for
osteoporosis. Cases of invasive pulmonary aspergillosis and central
nervous system disease have been reported in patients receiving
systemic corticosteroids for the treatment of ABPA (60–62).
ANTIFUNGAL AGENTS
To decrease the burden of fungal organisms and prevent
continued antigenic stimulation and subsequent inflammation,
antifungal therapies such as nystatin, amphotericin B, natamy-
cin, and ketoconazole have been tried (2, 27). Ketoconazole
showed some benefit but was associated with significant side
effects. Itraconazole has been used with greater success and
tolerability (5, 63–69). A number of case reports and a few
randomized studies attest to its beneficial effects (Table 4).
Current recommendations are to consider it as a corticosteroid-
sparing agent or if corticosteroids alone are ineffective (2, 62).
Itraconazole is administered at a dose of 200 mg twice daily for
4 to 6 months, then tapered over 4 to 6 months. Serum levels
drawn 4 hours after a dose after 1 to 2 weeks of therapy should
be checked in patients with severe disease or not responding to
therapy or in those on medications that might interact with
itraconazole.
Voriconazole, a newer antifungal azole with greater bio-
availability, has the potential to be more effective, with case
reports attesting to its benefit (70–73). It is given at a dose of
200 mg twice daily. The authors have personal experience with
its use in a patient with long-standing asthma who was treated
with voriconazole for presumed invasive aspergillosis. By the
time the patient was correctly diagnosed with ABPA, he had
resolution of ABPA-related clinical and radiographic abnor-
malities, with serum total IgE falling from 7,822 IU/ml to 2,243
IU/ml on voriconazole treatment alone. Antifungal therapy
should be considered as a corticosteroid-sparing agent or for
patients who have not responded to corticosteroids alone.
PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY VOL 7 2010
Adverse effects of azole therapy include nausea, vomiting,
diarrhea, fever, rash, headaches, fatigue, and decreased libido.
Elevations in transaminase levels occur and are usually tran-
sient, but liver failure has been reported, and monitoring liver
enzymes is advised. Drug interactions have been reported with
numerous agents including midozolam, cyclosporine, tacroli-
mus, oral hypoglycemic agents, and methylprednisolone but not
prednisone (4, 74). Agents that lower gastric acid may decrease
the effectiveness of these agents. Response to therapy is
assessed by the criteria outlined above.
MONOCLONAL ANTIBODY AGAINST IgE
Case reports of improvement with omalizumab suggest that
anti-IgE therapy may be of benefit (75, 76). In addition to the
risk of anaphylaxis, a recent FDA advisory suggests that cardiac
and thromboembolic events may occur with increased fre-
quency in patients using omalizimab (77). We do not recom-
mend this therapy based on the limited evidence for benefit and
potential toxicity.
ALLERGEN AVOIDANCE
Although aspergillus is ubiquitous, identification of environ-
mental sources that are particularly high in or support the active
growth of aspergillus is advised but may not be possible.
Remediation should be considered, although definite evidence
of benefit is lacking. Theoretically, this may reduce the ongoing
antigen exposure. Marijuana use may be an unidentified risk
factor, with case reports attesting to an association of marijuana
smoking and aspergillus exposure (78).
CONCLUSIONS
ABPA is a complex hypersensitivity response to A. fumigatus in
atopic patients with CF or asthma. It is characterized by
worsening symptoms, serum eosinophilia, and fleeting pulmonary
opacities on radiographs. An elevated serum total IgE, central
bronchiectasis, and hyperattenuating mucus on chest CT scan
heightens the suspicion for ABPA. The pathophysiology of
ABPA is allergic in nature, characterized by activation of
eosinophils and elaboration of IgE. Immune suppression there-
fore is the mainstay of treatment. Early identification allows
treatment with corticosteroids with a potential role for newer
antifungal azole medications as corticosteroid-sparing agents,
which may improve the long-term outcome in this potentially
relapsing condition.
Conflict of Interest Statement: K.P. does not have a financial relationship with
a commercial entity that has an interest in the subject of this manuscript. M.E.S.
received grant support from AstraZeneca, GlaxoSmithKline, and Novartis.
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