Chest: Allergic Bronchopulmonary Aspergillosis

Allergic Bronchopulmonary
Aspergillosis*
Ritesh Agarwal, MD, DM, FCCP
Allergic bronchopulmonary aspergillosis (ABPA) is an immunologic pulmonary disorder caused
by hypersensitivity to Aspergillus fumigatus. Clinically, a patient presents with chronic asthma,
recurrent pulmonary infiltrates, and bronchiectasis. The population prevalence of ABPA is not
clearly known, but the prevalence in asthma clinics is reported to be around 13%. The disorder
needs to be detected before bronchiectasis has developed because the occurrence of bronchiec-
tasis is associated with poorer outcomes. Because many patients with ABPA may be minimally
symptomatic or asymptomatic, a high index of suspicion for ABPA should be maintained while
managing any patient with bronchial asthma whatever the severity or the level of control. This
underscores the need for routine screening of all patients with asthma with an Aspergillus skin
test. Finally, there is a need to update and revise the criteria for the diagnosis of ABPA. This
review summarizes the advances in the diagnosis and management of ABPA using a systematic
search methodology. (CHEST 2009; 135:805826)
Key words: allergic bronchopulmonary aspergillosis; Aspergillus; bronchial asthma; cystic fibrosis; prevalence
Abbreviations: AAS allergic Aspergillus sinusitis; ABPA allergic bronchopulmonary aspergillosis; ABPA-CB allergic
bronchopulmonary aspergillosus with central bronchiectasis; ABPA-CB-ORF allergic bronchopulmonary aspergillosus with
central bronchiectasis and other radiological findings; ABPA-S seropositive allergic bronchopulmonary aspergillosus;
AHAspergillus hypersensitivity; CF cystic fibrosis; HRCT high-resolution CT; IL interleukin
A
spergillus is a ubiquitous mold representing be-
tween 0.1% and 22% of the total air spores
sampled.
1
There are approximately 250 species of
Aspergillus, but only a few are human pathogens.
2,3
Depending on the host immunity and the organism
virulence, the respiratory diseases caused by As-
pergillus are classified as saprophytic (aspergilloma),
allergic (allergic Aspergillus sinusitis, allergic bron-
chopulmonary aspergillosis [ABPA], and hypersensitiv-
ity pneumonias) and invasive (airway invasive aspergil-
losis, chronic necrotizing pulmonary aspergillosis, and
invasive aspergillosis).
4
ABPA is an allergic pulmonary
disorder caused by hypersensitivity to Aspergillus fu-
migatus clinically manifesting as chronic asthma, recur-
rent pulmonary infiltrates, and bronchiectasis.
513
The
condition has immunologic features of immediate hy-
persensitivity (type I), antigen-antibody complexes
(type III), and eosinophil-rich inflammatory cell
responses (type IVb), based on the revised Gell and
Coombs classification of immunologic hypersensitiv-
ity.
14,15
The disorder was first described by Hinson et
al
16
in 1952 in the United Kingdom. Occasionally,
patients can develop a syndrome similar to ABPA,
but it is caused by fungi other than A fumigatus and
is called allergic bronchopulmonary mycosis.
17
The
prevalence of ABPA is believed to be about 1 to 2%
in patients with asthma and 2 to 15% in patients with
cystic fibrosis (CF).
13
The condition remains underdi-
agnosed in many countries with reports of mean diag-
nostic latency of even 10 years between the occurrence
of symptoms and the diagnosis.
18
In the past two
decades, there has been an increase in the number
of cases of ABPA due to the heightened physician
awareness and the widespread availability of sero-
logic assays.
1923
This review provides a summary of
the advances in the field of ABPA. For the purpose of
this review, a systematic search of PubMed and Em-
*From the Department of Pulmonary Medicine, Postgraduate
Institute of Medical Education and Research, Chandigarh, India.
The author has no conflicts of interest to disclose.
Manuscript submitted November 4, 2008; revision accepted
November 20, 2008.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Ritesh Agarwal, MD, DM, FCCP, Assistant
Professor, Department of Pulmonary Medicine, Postgraduate
Institute of Medical Education and Research, Sector-12, Chandi-
garh 160012, India; e-mail: riteshpgi@gmail.com
DOI: 10.1378/chest.08-2586
CHEST Global Medicine
www.chestjournal.org CHEST / 135 / 3 / MARCH, 2009 805
Downloaded From: http://journal.publications.chestnet.org/ by a Alfred Hospital User on 05/02/2014
Base was performed for relevant studies published from
1952 to 2008. Atotal of 250 articles were reviewed for the
purpose of this article.
Epidemiology of ABPA
Aspergillus hypersensitivity (AH) is defined by the
presence of an immediate-type cutaneous hypersen-
sitivity to A fumigatus antigens, and it is the first step
in the development of ABPA.
24
Only a minority of
patients with AH develop the complete clinical
picture of ABPA.
25
The population prevalence of
ABPA in asthma, generally referred to as 1 to
2%,
5,13,26,27
is based on the inference of only three
studies (one peer-reviewed and two nonpeer-re-
viewed studies).
28,29
In the only peer-reviewed
study,
28
14 patients with allergic bronchopulmonary
mycosis were identified from a total of 1,390 new
referrals in a catchment area population of half a
million, estimating a period prevalence of just above
1%. The other two nonpeer-reviewed question-
naire-based studies suggested a maximum preva-
lence of ABPA of 1% in the United States.
29
In a
recent metaanalysis,
30
we demonstrated a prevalence
of AH and ABPA in asthma of 28% and 12.9%,
respectively. The limitation noted in this review was
that all the studies were performed in specialized
clinics and may not be representative of the general
population. Thus the exact population prevalence of
ABPA remains speculative but is likely to be fairly
high in patients attending asthma clinics. Table 1
summarizes the prevalence of ABPA in patients with
asthma reported in various studies
20,23,3136
over the
last two decades. The prevalence of ABPA in pa-
tients admitted with acute severe asthma is even
higher. In a recent study of 57 patients with acute
severe asthma admitted in the respiratory ICUs, we
demonstrated the prevalence of AH and ABPA to be
around 51% and 39%, respectively.
37
The occurrence
of AH and ABPA was significantly higher in patients
with acute asthma compared to the outpatient bron-
chial asthma (around 39% and 21%, respectively).
23
Pathogenesis of ABPA
The susceptibility of asthmatic patients to develop
ABPA is not fully understood (Fig 1). Some authors
have reported that exposure to large concentrations
of spores of A fumigatus may cause ABPA.
16,3841
Environmental factors are not considered the main
pathogenetic factors because not all asthmatics de-
velop ABPA despite being exposed to the same
environment. In a genetically predisposed individu-
al
4254
(Table 2), inhaled conidia of A fumigatus
persist and germinate into hyphae with release of
antigens that compromise the mucociliary clearance,
stimulate and breach the airway epithelial barrier,
and activate the innate immunity of the lung.
5558
This leads to inflammatory cell influx and a resultant
early- and late-phase inflammatory reaction.
59,60
The
Table 1Studies Describing the Prevalence of AH and/or ABPA in Patients with Bronchial Asthma Over the Last
Two Decades*
Study/Year Type of Study
Type of Skin
Test Type of Antigen
Criteria Used for
Diagnosis of ABPA
Prevalence of AH
in Asthma (n/N)
Prevalence of ABPA
in Asthma (n/N)
Attapattu
31
/1991 Prospective Intradermal Commercial (Bencard
Allergie; Munich,
Germany)
Major (A/R/T/E/P)
Minor (C)
58/134 8/134
Eaton et al
33
/2000 Prospective Prick Commercial (Hollister-
Stier Laboratories)
Major (A/R/T/E/P/
I/C/S)
47/255 9/35
Kumar and Gaur
34
/
2000
Prospective Intradermal Locally prepared Major (A/R/T/E/P/
I/C/S)
47/200 32/200
Minor (C/S/B)
Al-Mobeireek et al
20
/
2001
Prospective Prick Commercial (Soluprick;
ALK Laboratories;
Wallingford, CT)
12/53
Maurya et al
35
/2005 Prospective Intradermal Locally prepared Major (A/R/T/E/P/
I/C/S)
30/105 8/105
Minor (C/S)
Agarwal et al
23
/2007 Prospective Intradermal Commercial (Hollister-
Stier Laboratories)
Major (A/R/T/E/P/
I/C/S)
291/755 155/755
Minor (S/B)
Prasad et al
36
/2008 Prospective Intradermal Not available Major (A/R/T/E/P/
I/C/S)
74/244 18/244
Minor (C/S/B)
* Criteria for ABPA: Major (A asthma, R radiologic opacities, T immediate positive skin test, E eosinophilia, P precipitins to A
fumigatus, I IgE elevated, C central bronchiectasis, S specific IgG/IgE to A fumigatus); Minor (C sputum cultures of A fumigatus,
S type III skin test positivity, B brownish black mucus plugs).
806 Global Medicine
antigens are also processed presented to T-cells with
activation of Th2 CD4T-cell responses.
42,6163
The Th2
cytokines (interleukin [IL]-4, IL-5, and IL-13) lead to total
and A fumigatus-specific IgE synthesis, mast cell degran-
ulation, and promotion of a strong eosinophilic response.
This causes the characteristic pathology of ABPA.
Pathology of ABPA
The pathology of ABPA varies from patient to
patient, and in different areas of the lung in the same
patient (Fig 2).
64,65
Histologic examination reveals
the presence of mucus, fibrin, Curschmann spirals,
Charcot-Leyden crystals, and inflammatory cells.
Scanty hyphae can often be demonstrated in the
bronchiectatic cavities. The bronchial wall in ABPA
is usually infiltrated by inflammatory cells, primarily
the eosinophils.
65
The peribronchial parenchyma
shows an inflammatory response with conspicuous
eosinophilia. Occasionally, fungal growth in the lung
parenchyma can occur in some patients with ABPA.
66
Patients can also demonstrate a pattern similar to that
of bronchiolitis obliterans with organizing pneumo-
nia.
67
Bronchocentric granulomatosis, the presence of
noncaseating granulomas containing eosinophils and
Figure 1. Aline diagramdepicting the pathogenesis of allergic bronchopulmonary aspergillosis. Th T-helper.
multinucleated giant cells centered on the airway, are
also seen.
68,69
Rarely, invasive aspergillosis complicat-
ing the course of ABPA has also been described.
7074
Clinical Features
There is no gender predilection and majority of the
cases present in the third to fourth decade. A family
history of ABPA may be elicited occasionally.
75
Table 3
summarizes the clinical features of ABPA encoun-
tered in three large series from our institute.
19,21,23
Most present with low-grade fever, wheezing, bron-
chial hyperreactivity, hemoptysis, or productive
cough. Expectoration of brownish black mucus plugs
is seen in 31 to 69% of patients.
21,23,34
The symptoms
of hemoptysis, expectoration of brownish black mu-
cus plugs, and history of pulmonary opacities in an
asthmatic patient suggests ABPA. Patients can oc-
casionally be asymptomatic, and the disorder is
diagnosed on routine screening of asthmatic pa-
tients.
22,23,33
Physical examination can be normal or
may reveal polyphonic wheeze. Clubbing is rare,
seen in only 16% of patients. On auscultation, coarse
crackles can be heard in 15% of patients.
23
Physical
examination can also detect complications such as
pulmonary hypertension and/or respiratory failure.
76
During exacerbations of ABPA, localized findings of
consolidation and atelectasis can occur that needs to
be differentiated from other conditions.
Laboratory Findings
Aspergillus Skin Test: The Aspergillus skin test is
performed using an A fumigatus antigen, either
commercial (eg, Aspergillin; Hollister-Stier Labora-
tories; Spokane, WA) or locally prepared. The test is
read every 15 min for 1 h, and then after 6 to 8 h.
The reactions are classified as type I if a wheal and
erythema developed within 1 min, reaches a maxi-
mum after 10 to 20 min, and resolves within 1 to 2 h.
A type III reaction is read after 6 h, and any amount
of subcutaneous edema is considered a positive
result. An immediate cutaneous hypersensitivity to A
fumigatus antigens is a characteristic finding of
ABPA and represents the presence A fumigatus-
specific IgE antibodies, whereas a type III skin
reaction probably represents the immune complex
hypersensitivity reaction, although its exact signifi-
cance remains unclear. The test can be performed
using either a skin-prick test or intradermal injection
with the latter being more sensitive.
30,77,78
A skin-
prick test should be performed for Aspergillus skin
testing, and if the results are negative should be
confirmed by an intradermal test.
30
There is no
difference on the outcome of the test and the type of
antigen (locally prepared or commercial) used for
performance of the test.
30
Total Serum IgE Levels: The total IgE level is the
most useful test for diagnosis and follow-up of ABPA. A
normal serum IgE level excludes ABPA as the cause of
the patients current symptoms. The only situation
where IgElevels can be normal in active ABPA is when
the patient is already on glucocorticoid therapy for any
reason and investigation for IgE levels has been con-
ducted. After treatment with glucocorticoids, the se-
rum IgE levels decline, and a 35 to 50% decrease is
taken as a criteria for remission.
79
The serum IgE
determination is also used for follow-up, and a doubling
of the patients baseline IgE levels indicates relapse of
ABPA.
80,81
Table 2Genetic Factors Involved in the Pathogenesis
of ABPA*
HLA associations: presence of HLA DR-2 and absence of
HLA-DQ2 sequences
42,44,45
IL-10 promoter polymorphisms
49
Polymorphism at position 1,082 produces higher levels of IL-10
if 1082G allele is present and lower levels of IL-10 if the
1082A allele is present
In patients with CF there is a relationship between the 1082GG
genotype with both Aspergillus colonization and ABPA
Surfactant protein A gene polymorphisms
48,53
A significantly higher frequency of the AGA allele (A1660G) of
SP-A2 found in patients with ABPA vs control subjects.
Coexistence of A1660G polymorphism with SP-A2 G1649C
(Ala91Pro) found with 10-fold higher odds in patients with
ABPA. Patients with ABPA with GCT and AGG alleles
showed significantly higher levels of total IgE and percentage
eosinophilia vs patients with ABPA with CCT and AGA
alleles
48
The T allele at T1492C and G allele at G1649C of SP-A2
observed at higher frequencies in ABPA patients than in
controls. Also there is a higher frequency of the TT genotype
at position1492 of SP-A2 than controls
53
There were no polymorphisms found in SP-A1 gene
53
CFTR gene mutation:
43,46,47
increased frequency of CFTR
mutations in patients with ABPA vs skin-prick test positive or
negative patients with bronchial asthma
IL-15 polymorphisms:
52
higher frequency of IL-15 13689*A
allele and A/A genotype
TNF- polymorphisms:
52
lower frequency of the TNF- 308 * A/A
genotype
Mannose-binding lectins:
53
the intronic single nucleotide
polymorphism G1011A of mannose-binding lection seen with
increased frequency in patients with ABPA
IL-4 receptor polymorphisms:
51
single nucleotide polymorphism of
the extracellular IL-4R ile75val observed in 80% of ABPA
patients
IL-13 polymorphisms:
50
the arg110gln polymorphism found with
increased frequency in ABPA and the combination of IL-4R
ile75val/IL-13 arg110gln polymorphism found with an even
higher frequency
Toll-like receptor gene polymorphisms:
54
susceptibility to ABPA
was associated with allele C on T1237C (TLR9)
*HLA human leukocyte antigen; TNF tumor necrosis factor;
CFTR CF transmembrane conductance regulator.
808 Global Medicine
Serum IgE and IgG Antibodies Specific to A
fumigatus: An elevated level of A fumigatus-specific
antibodies measured by fluorescent enzyme immuno-
assay is considered the hallmark of ABPA.
22
A
cutoff value of IgG/IgE more than twice the pooled
serum samples from patients with AH can greatly
help in the differentiation of ABPA from other
conditions.
82
Table 3Clinical Features Encountered in Three Large Case Series of ABPA Published From the Authors
Institute*
Clinical Features Behera et al
19
/1994 Chakrabarti et al
21
/2002 Agarwal et al
23
/2007
Patients, No. 35 89 155
Male/female gender, No. 14/21 53/35 79/76
Mean age, yr 34.3 36.4 33.4
Mean duration of asthma, yr 11.1 12.1 8.9
History of asthma 94% 90% 100%
Expectoration of sputum plugs Not available 69% 46.5%
Mean eosinophil count, per L 1,264
AEC 500/L, % 12/28 (43%) 100% 76.1%
Fleeting shadows 77% 74% 40%
History of intake of antituberculous drugs 34% 29% 44.5%
Skin test against Aspergillus
Type I 51% 85% 100%
Type III 25.7% 16.9% 83.2%
Mean IgE levels Not done Not done 6,434
Elevated IgE levels, % 100%
Aspergillus-specific IgE/IgG Not done Not done 100%
Serum precipitins against Aspergillus 77% 71.9% 86.5%
Central bronchiectasis 71% 69% 76.1%
*AEC absolute blood eosinophil count.
Figure 2. Histopathologic findings in a patient with allergic bronchopulmonary aspergillosis. Top left, A:
photomicrograph showing bronchial lumen containing allergic mucin (hematoxylin-eosin, original 100). Top
right, B: high-magnification photomicrograph of allergic mucin having variegated appearance, necrotic eosino-
phils, Charcot-Leyden crystals (thin arrow), and an occasional septate fungal hyphae indicated by a thick arrow
(hematoxylin-eosin, original 200). Bottom left, C: photomicrograph showing eosinophilic pneumonia. There is
filling of the alveolar spaces by eosinophils admixed with variable number of macrophages (hematoxylin-eosin,
original 200). Bottom right, D: photomicrograph showing bronchocentric granulomatosis. There is partial
replacement of bronchial epithelium by palisading histiocytes (hematoxylin-eosin, original 100).
Radiologic Investigations: A wide spectrum of
radiographic appearances can occur in ABPA (Table
4). The chest radiographic findings of ABPA include
transient or fixed pulmonary opacities (Fig 3), tram-
line shadows, finger-in-glove opacities, and tooth-
paste shadows.
8387
Findings noted on high-resolution
CT (HRCT) include central bronchiectasis, mucoid
impaction, mosaic attenuation, presence of centri-
lobular nodules, and tree-in-bud opacities (Fig
4).
88,89
High-attenuation mucoid impaction (mucus
visually denser than the paraspinal muscle) is a
pathognomonic finding encountered in patients with
ABPA.
23,9095
Central bronchiectasis with peripheral
tapering of bronchi on HRCT is believed to be a sine
qua non for the diagnosis of ABPA. Bronchiectasis
may not be present in all patients with ABPA, may be
present in patients with CF without ABPA, and
almost 40% of the bronchiectatic segments can also
have associated peripheral bronchiectasis.
22,96
Mini-
mal bronchiectasis can also be seen in asthma,
97,98
but the findings of bronchiectasis affecting three or
more lobes, centrilobular nodules, and mucoid im-
paction are highly suggestive of ABPA.
99
The un-
common radiologic manifestations of ABPA include
miliary nodular opacities,
100
perihilar opacities
simulating hilar lymphadenopathy,
84,101,102
pleural
effusions,
103105
and pulmonary masses.
106111
Serum Precipitins Against A fumigatus: The pre-
cipitating IgG antibodies are elicited from crude
extracts of A fumigatus and can be demonstrated
using the double gel diffusion technique.
112,113
They
can also be present in other pulmonary disorders and
thus represent supportive not diagnostic evidence for
ABPA.
112114
Peripheral Eosinophilia: A blood absolute eosino-
phil count 1,000 cells/L is also a major criterion
for the diagnosis of ABPA. However, 53% of patients
in our series
22
had an absolute eosinophil count
1,000 cells/L, and thus a low eosinophil count
does not exclude the diagnosis of ABPA.
Sputum Cultures for A fumigatus: Culture of A
fumigatus in the sputum is supportive but not diag-
nostic of ABPA. The fungus can also be grown in
patients with other pulmonary diseases due to the
ubiquitous nature of the fungi. We rarely perform
sputum cultures for the diagnosis of ABPA.
Pulmonary Function Tests: These tests help cate-
gorize the severity of the lung disease but have no
diagnostic value in ABPA and need not constitute
the basis for screening.
22
The usual finding is an
obstructive defect of varying severity.
115117
Role of Specific Aspergillus Antigens: Patients with
ABPA are evaluated with crude extracts from As-
pergillus, which lack reproducibility and consistency,
and they frequently cross-react with other anti-
gens.
118
The advances in molecular techniques have
enabled detection and cloning of specific Aspergillus
antigens. The recombinant allergens Asp f1, Asp f2,
Asp f3, Asp f4, and Asp f6 have been evaluated for
their diagnostic performance in serologic studies in
asthmatic patients
119122
and in patients with
CF
121,123125
Preliminary data suggest a promising
role of these antigens in the diagnosis of ABPA.
Further studies are required before they can be
implemented in routine clinical practice.
Diagnosis and Diagnostic Criteria
The Rosenberg-Patterson criteria
6,9
are most often
used for the diagnosis (Table 5). There are also a set
Table 4Radiologic Findings Encountered in Patients
With ABPA
1. Chest radiographic findings
Transient changes
Common
Patchy areas of consolidation
Radiologic infiltrates: toothpaste and gloved finger shadows
due to mucoid impaction in dilated bronchi
Collapse: lobar or segmental
Uncommon
Bronchial wall thickening: tramline shadows
Air-fluid levels from dilated central bronchi filled with fluid
Perihilar infiltrates simulating adenopathy
Massive consolidation: unilateral or bilateral
Small nodules
Pleural effusions
Permanent changes
Common
Parallel-line shadows representing bronchial widening
Ring-shadows 12 cm in diameter representing dilated
bronchi en face
Pulmonary fibrosis: fibrotic scarred upper lobes with
cavitation
Uncommon
Pleural thickening
Mycetoma formation
Linear scars
2. HRCT findings
Common
Central bronchiectasis
Mucus plugging with bronchoceles
Consolidation
Centrilobular nodules with tree-in-bud opacities
Bronchial wall thickening
Areas of atelectasis
Mosaic perfusion with air trapping on expiration
Uncommon
High-attenuation mucus (finding most helpful in differential
diagnosis)
Pleural involvement
Randomly scattered nodular opacities
810 Global Medicine
of minimal diagnostic criteria for ABPA (Table
5).
32,33
These criteria continue to be challenged and
modified because there is lack of evidence on the
number of criteria that should be present to make
the diagnosis. The differentiation of patients with
ABPA from patients with AH can also be problem-
atic. Serum precipitins to A fumigatus is present in
69 to 90% of patients with ABPA
23,112,116,126,127
but
also in 9% of asthmatics.
112
can be seen in patients with asthma without
ABPA.
9799
There are no cutoffs for total IgE levels
with many using 1,000 IU/mL,
8,9,22,23,82,128130
and
others using 1,000 ng/mL (equivalent to 417 IU/
mL).
5,27,33,34
The total IgE levels may also be ele-
vated in patients with AH without ABPA. As the
understanding of ABPA has evolved, it is clear that
patients with AH may present with less than the full
complement of diagnostic criteria.
131
Thus, a cutoff
value of 1,000 ng/mL IgE will probably lead to an
overdiagnosis of ABPA.
131
The use of A fumigatus-
Figure 4. HRCT images of different patients with allergic bronchopulmonary aspergillosis. Top right:
bilateral central bronchiectasis with centrilobular nodules and tree-in-bud opacities in the left lung. Top
left: bilateral central bronchiectasis with many mucus-filled bronchi. Bottom, left and right: images from
the same patient show high-attenuation mucoid impaction. Bottom right: the mucoid impaction in the
right lung is visually denser than the paraspinal skeletal muscle.
Figure 3. Chest radiograph showing transient pulmonary opacities in the right lower lobe (left) in a
patient with allergic bronchopulmonary aspergillosis that have spontaneously disappeared (right).
specific IgE and IgG levels can help in confirming
the diagnosis of ABPA because values of IgG/IgE
more than twice the pooled serum samples from
patients with asthma are raised only in ABPA.
113,132
We currently use a cutoff value of 1,000 IU/mL for
the diagnosis of ABPA.
22,23
While investigating a
patient with asthma, we first perform an Aspergillus
skin test. Once it is positive, the total serum IgE
levels are done.
131
If the value is 1,000 IU/mL, we
perform the other tests (Fig 5). If the value is
between 500 and 1,000 IU/mL, the next step is analysis
of A fumigatus-specific IgE and IgG antibodies. If the
levels are raised, the patient is followed up every 6 weeks
with total IgE levels. If the absolute value rises 1,000
IU/mLor there is a rising trend with clinical deterioration,
the treatment is started. If the value is between 500 and
1,000 IU/mLand IgEand IgGspecific to Afumigatus are
not raised, the patient is followed up with a yearly total
IgE levels (Fig 5).
Natural History
The natural history of ABPA is not well character-
ized.
9,128,133136
An early diagnosis and initiation of
systemic corticosteroids are essential to prevent irre-
versible damage.
137
The natural course of ABPA can
be best understood if we recognize the two impor-
tant classification schemes (Tables 6 and 7) of ABPA:
(1) classification of ABPA into five stages as de-
scribed by Patterson et al
8
, and (2) classification of
ABPA into ABPA-S (seropositive ABPA) and ABPA-CB
(ABPA with central bronchiectasis) described by
Greenberger et al.
12
Staging of ABPA: ABPA has been classified into
five stages, but a patient does not necessarily
progress from one stage to the other sequentially
(Table 6). Patients in stage I or III (depending on
whether or not the disorder has been previously
diagnosed) are generally symptomatic with radio-
graphic infiltrates, raised IgE levels, and elevated A
fumigatus-specific IgG/IgE.
23
With glucocorticoid
therapy, there is clearing of radiographic opacities
with a 35 to 50% decline in IgE levels by 6 weeks
that defines remission or stage II. The aim of
glucocorticoid therapy is not normalization of total
IgE levels because the immunologic process goes in
remission with just 35 to 50% decline in IgE levels,
and in many patients the IgE levels do not come to
down to normal values. The test needs to be often
repeated during therapy to determine the lowest
level for an individual patient that serves as the
baseline for that particular patient. Treatment is
continued for 6 to 9 months, and if there are no
exacerbations over the next 3 months after stopping
therapy, we label it as complete remission. Patients
in complete remission are followed up by serial IgE
levels every 6 months for the first year and then
annually. Even in patients with complete remission,
the IgE levels decline to normal in only a minority of
patients,
128,133
and the aim of glucocorticoid therapy
is not achievement of normal IgE levels.
79
A com-
plete remission does not imply a permanent remis-
sion because exacerbations can occur several years
after remission.
135
Almost 25 to 50% of the patients
have relapse/exacerbation of the disease, defined by
doubling of the baseline IgE levels (stage III).
8,9,22
Patients in stage IV require oral glucocorticoids for
control of asthma (glucocorticoid-dependent asthma)
or ABPA (glucocorticoid-dependent ABPA).
10,22
Pa-
tients in stage V are those with widespread bronchi-
ectasis and varying degrees of pulmonary dysfunc-
tion. We define patients in stage V if they have
hypercapnic respiratory failure (Pao
2
60 mm Hg
and Paco
2
45 mm Hg) and/or cor pulmonale.
Even in stage V ABPA, the disease can be clinically
as well as immunologically active requiring long-
term glucocorticoid therapy.
136,138
Table 5Criteria Used for the Diagnosis of ABPA
Rosenberg-Patterson criteria
6,9
Major criteria (mnemonic ARTEPICS)
A Asthma
R Roentgenographic fleeting pulmonary opacities
T Skin test positive for Aspergillus (type I reaction,
immediate cutaneous hyperreactivity)
E Eosinophilia
P Precipitating antibodies (IgG) in serum
I IgE in serum elevated ( 1,000 IU/mL)
C Central bronchiectasis
S Serums A fumigatus-specific IgG and IgE (more than
twice the value of pooled serum samples from patients with
asthma who have Aspergillus hypersensitivity)
Minor criteria
Presence of Aspergillus in sputum
Expectoration of brownish black mucus plugs
Delayed skin reaction to Aspergillus antigen (type III
reaction)
The presence of six of eight major criteria makes the diagnosis
almost certain; the disease is further classified as ABPA-S or
ABPA-CB on the absence or presence of central
bronchiectasis, respectively
Minimal diagnostic criteria for ABPA
32
Minimal ABPA-CB
Asthma
Immediate cutaneous hyperreactivity to Aspergillus antigens
Elevated IgE
Raised A fumigatus-specific IgG and IgE
Minimal ABPA-S
Asthma
Immediate cutaneous hyperreactivity to Aspergillus antigens
Transient pulmonary infiltrates on chest radiograph
Elevated IgE
Raised A fumigatus-specific IgG and IgE
812 Global Medicine
Radiologic Classification of ABPA: ABPA is clas-
sified as ABPA-S or ABPA-CB, respectively, de-
pending on the absence or presence of bronchiec-
tasis or as ABPA-S (mild), ABPA-CB (moderate),
and ABPA-CB-ORF (other radiologic findings)
(Table 7). Patients with ABPA-S probably repre-
sent the earliest stage of the disorder. It is be-
lieved that patients with ABPA-S have a milder
Figure 5. Algorithm followed in the diagnostic workup for allergic bronchopulmonary aspergillosis in the authors chest clinic.
clinical course and less severe immunologic find-
ings when compared to ABPA-CB based on the
inference of three studies (total of 124 pa-
tients).
12,139,140
In the largest of these three studies
(76 patients), only the A fumigatus-specific IgG
levels were higher in patients with ABPA-CB
compared to ABPA-S. Other immunologic param-
eters were not significantly different between the
two groups.
12
In our study of 126 patients, the
clinical, spirometric, and immunologic findings
were not significantly different when classifying
ABPA into ABPA-S and ABPA-CB or as ABPA-S,
ABPA-CB, and ABPA-CB-ORF.
22
However, the course of patients with ABPA-S is
likely to be less severe when compared to those with
ABPA-CB. In a multivariate analysis of 155 patients
with ABPA, we demonstrated that the severity of
bronchiectasis and presence of hyperattenuating
mucoid impaction on HRCT-predicted relapses of
ABPA and the severity of bronchiectasis was an
independent predictor of failure to achieve long-
term remission.
23
Thus it may not be important to
stage the severity of ABPA based on the presence
or absence of CB, but it remains prudent to
diagnose and treat ABPA early to prevent the
development of bronchiectasis because it in-
creases the probability of a smoother course of this
relapsing-remitting disorder.
Management
The management of ABPA includes two important
aspects: institution of glucocorticoids to control the
immunologic activity and close monitoring for detec-
tion of relapses. Another possible target is the use of
antifungal agents to attenuate the fungal burden
secondary to the fungal colonization in the airways.
Systemic Glucocorticoid Therapy: Oral corticoste-
roids are the treatment of choice for ABPA. They not
only suppress the immune hyperfunction but are also
antiinflammatory. There are no data to guide the
dose and duration of glucocorticoids, and different
regimens of glucocorticoids have been used (Table
8). The use of lower doses of glucocorticoids was
associated with frequent relapses or corticosteroid
dependence (45%).
9
We use a higher dosage of
glucocorticoids for a longer duration and observed
higher remission rates and a lower prevalence of
glucocorticoid-dependent ABPA (13.5%).
22
This
raises the possibility of a higher dose and prolonged
duration of corticosteroid therapy being associated
Table 6Stages of ABPA
8,22
Stage Description Clinical Picture Radiologic Findings Immunologic Features
I Acute phase Usually symptomatic,
fever, weight loss,
wheeze
Normal or presence of
radiologic opacities
IgE 1,000 IU/mL, raised
specific IgG/IgE and
precipitins to A fumigatus
II Remission Asymptomatic Generally normal or significant
resolution of radiologic
opacities from the acute
phase
Usually 3550% decline in IgE
levels by 6 wk to 3 mo; we
give additional label of
complete remission if the
patient did not have any
additional ABPA exacerbations
over the next 3 mo after
stopping steroid therapy
III Exacerbation Symptomatic as in acute
phase
Transient or fixed pulmonary
opacities
Doubling of IgE levels from
baseline
IV Glucocorticoid-dependent
ABPA
Symptomatic Transient or fixed pulmonary
opacities
Two groups can be identified:
one in whom IgE levels do not
rise but require steroids for
asthma control (glucocorticoid-
dependent asthma); the other
in whom steroids are required
to continually suppress the
disease activity (glucocorticoid-
dependent ABPA)
V End-stage (fibrotic)
ABPA
Symptomatic, findings of
fixed airway
obstruction, severe
pulmonary
dysfunction, type II
respiratory failure, cor
pulmonale
Evidence of bronchiectasis,
pulmonary fibrosis,
pulmonary hypertension
Serum IgE levels and specific
immunoglobulins do not
become normal in most
patients, and even these
patients can have frequent
exacerbations
814 Global Medicine
with better outcomes. However, there are no direct
comparisons between the two regimens, and the
selection is a matter of personal preference. The
clinical effectiveness of steroid therapy is reflected
by marked decreases in the patients total serum IgE
levels (there seems to be no correlation between
serum levels of A fumigatus-specific IgE levels and
disease activity
141
) along with symptom and radio-
graphic improvements. The goal of therapy is not to
attempt normalization of IgE levels but to decrease
the IgE levels by 35 to 50%, which leads to clinical
and radiographic improvement. One should also
establish a stable serum level of total IgE to serve as
a guide to future detection of relapse.
Inhaled Corticosteroids: Although small case stud-
ies suggest some benefit of inhaled corticosteroids in
the management of ABPA,
142145
a double-blind mul-
ticenter placebo-controlled trial in 32 patients sug-
gested no superiority over placebo.
146
We use inhaled
corticosteroids only for the control of asthma once the
oral prednisolone dose is reduced to 10 mg/day.
Oral Itraconazole: Ketoconazole has been tried in
the past
147
and has been replaced by the less toxic
agent, itraconazole.
130,141,148160
Only two random-
ized controlled studies (84 patients) have evaluated
the role of itraconazole in ABPA.
130,156
Pooled anal-
ysis showed that itraconazole could significantly de-
crease the IgE levels by 25% when compared to
placebo but did not cause significant improvement in
lung function.
161
A major limitation was that neither
of the studies reported long-term outcomes in
ABPA. Thus longer term trials are required before a
firm recommendation can be made for the use of
itraconazole in ABPA. We currently use itraconazole
only after the first relapse of ABPA despite glucocor-
ticoid therapy or in patients with glucocorticoid-
dependent ABPA (Table 8). In the limited numbers
of patients in whom we have used the drug, there
was no observable advantage.
22
Itraconazole not only
has numerous adverse effects,
162
but it also inhibits
the metabolism of methylprednisolone (but not
prednisolone) with resultant increased frequency of
Table 7Radiologic Classification of ABPA*
Classification Features
Greenberger et al
12
classification
ABPA-S All the diagnostic features of ABPA
but no evidence of central
bronchiectasis on HRCT.
Patients with ABPA-S may be
classified as Patterson stages I to
IV. These patients may have
recurrent exacerbations and may
also be classified as stage III
(ABPA-CB) All findings of ABPA including CB
on HRCT. Patients with ABPA-
CB may belong to any of the
Patterson stages
Kumar
140
classification
ABPA-S ABPA without CB
ABPA-CB ABPA with CB
ABPA-CB-ORF ABPA with CB other radiologic
features such as pulmonary
fibrosis, bleb, bullae,
pneumothorax, parenchymal
scarring, emphysematous change,
multiple cyst, fibrocavitary
lesions, aspergilloma, ground-
glass appearance, collapse,
mediastinal lymph node, pleural
effusion, and pleural thickening
*Both the classification schemes believe that patients without CB and
ORF have serologically milder disease, but it has been shown that
there is no difference in clinical, spirometric, and serological
severity between patients with and without bronchiectasis (see text
for details).
Table 8Treatment Protocols for the Management of
ABPA
Oral glucocorticoids
Regime 1
5
Prednisolone, 0.5 mg/kg/d, for 12 wk, then on alternate days
for 68 wk. Then taper by 510 mg every 2 wk and
discontinue
Repeat the total serum IgE concentration and chest
radiograph in 6 to 8 wk
Regime 2
22,113
Prednisolone, 0.75 mg/kg, for 6 wk, 0.5 mg/kg for 6 wk, then
tapered by 5 mg every 6 wk to continue for a total duration
of at least 6 to 12 mo. The total IgE levels are repeated
every 6 to 8 wk for 1 yr to determine the baseline IgE
concentrations
Follow-up and monitoring
The patients are followed up with a medical history and
physical examination, chest radiograph, and measurement of
total IgE levels every 6 wk to demonstrate decline in IgE
levels and clearing of the chest radiograph
A 35% decline in IgE level signifies satisfactory response to
therapy. Doubling of the baseline IgE value can signify a
silent ABPA exacerbation
If the patient cannot be tapered off prednisolone, the disease
has evolved into stage IV. Management should be
attempted with alternate-day prednisone with the least
possible dose
Monitor for adverse effects (eg, hypertension, secondary
diabetes)
Prophylaxis for osteoporosis: oral calcium and bisphosphonates
Oral itraconazole
Dose: 200 mg bid for 16 wk then once a day for 16 wk
Indication: First relapse of ABPA or glucocorticoid-dependent
ABPA
Follow-up and monitoring
Monitor for adverse effects (eg, nausea, vomiting, diarrhea,
and elevated liver enzymes)
Monitor for drugdrug interactions
Monitor clinical response based on clinical course,
radiography, and total IgE levels
steroid side effects including adrenal insufficiency.
163
Adrenal suppression has also been reported with the
concomitant use of itraconazole and inhaled budes-
onide.
164,165
Other Therapies: There is a single patient case
report of ABPA treated with inhaled amphotericin
and budesonide.
166
Similarly, there is another case
record on the use of omalizumab for the manage-
ment of ABPA.
167
One author has also used pulse
doses of IV methylprednisolone for the treatment of
severe ABPA.
168
Recently, voriconazole has also
been tried in the treatment of ABPA.
169171
Differential Diagnosis and Complications
The disorder needs to be differentiated from the
following conditions: Aspergillus hypersensitive
bronchial asthma, pulmonary tuberculosis in en-
demic areas, community-acquired pneumonia (espe-
cially acute presentations), and other inflammatory
pulmonary disorders such as eosinophilic pneumo-
nia, bronchocentric granulomatosis, and Churg-
Strauss syndrome. The complications of ABPA in-
clude recurrent asthma exacerbations and, if
untreated, the development of bronchiectasis with
subsequent pulmonary hypertension and respiratory
failure. In fact, this is the reason why routine screen-
ing is recommended in bronchial asthma to prevent
the complications just described.
ABPA in Special Situations
ABPA Complicating CF: The association of ABPA
and CF was first reported in 1965.
172
The occur-
rence of ABPA in CF is associated with deterioration
of lung function, higher rates of microbial coloniza-
tion, pneumothorax, massive hemoptysis, and poorer
nutritional status.
153,173,174
A key element in the
immunopathogenesis may be exposure to high levels
of Aspergillus allergens due to abnormal mucus
properties.
175
The recognition of ABPA in CF can be
difficult because ABPA shares many clinical charac-
teristics with poorly controlled CF lung disease.
Presence of wheezing, pulmonary infiltrates, bron-
chiectasis, and mucus plugging are common mani-
festations of CF-related pulmonary disease without
ABPA. The prevalence of AH in patients with CF
Table 9Studies Describing Prevalence of AH and/or ABPA in Patients With CF
Study Year Nature of Study Patients, No. AH in CF ABPA* in CF Diagnosis of AH
Mearns et al
184
1967 Prospective 86 28/86 Skin test
Allan et al
185
Silverman et al
186
1978 Prospective 48 17 Skin test
Nelson et al
187
1979 Prospective 46 18/46 5/46 Skin test
Laufer et al
177
Feanny et al
188
Schonheyder et al
189
1988 Prospective 200 10/200
Zeaske et al
190
Knutsen et al
176
Nicolai et al
179
1990 Prospective 148 58/148 Serology
Simmonds et al
191
Hutcheson et al
192
el-Dahr et al
193
1994 Prospective 147 30/147 22/147 Serology
Marchant et al
194
1994 Retrospective 160 16/160 Skin test
Mroueh and Spock
178
1994 Retrospective 236 38/87 15/236 Skin test
Becker et al
181
Hutcheson et al
195
Geller et al
182
1999 Prospective 14,210 281/14,210
Nepomuceno et al
153
1999 Retrospective 172 16/172
Cimon et al
196
Mastella et al
174
2000 Prospective 12,447 967/12,447
Taccetti et al
197
2000 Prospective 3,089 191/3,089
Ritz et al
180
2005 Prospective 160 20/160 11/160 Serology
Skov et al
183
Almeida et al
198
Kraemer et al
173
Chotirmall et al
199
Rapaka and Kolls
200
* ABPA: Studies have used different inclusion criteria for diagnosing ABPA. See text for further details.
AH: Defined as immediate cutaneous hypersensitivity to Aspergillus antigen or a positive specific IgE in serum against A fumigatus
(radioallergosorbent test class 2) and/or increased specific IgE in serum against rAsp f1 9.6 EU/mL, with normal values for rAsp f4 ( 8.4
EU/mL) and rAsp f6 ( 7.2 EU/mL)
816 Global Medicine
has been reported between 29% and 53%,
176180
and
the prevalence of ABPA as 1 to 15%. Atopy seems to
be an important risk factor for ABPA in CF, with
ABPA observed in 22% of atopic patients but only
2% of nonatopic patients.
153,181183
To determine the prevalence of AH/ABPA in CF,
a systematic search was performed. The search
yielded 28 studies (16 studies [1,391 patients] de-
scribing the prevalence of AH in CF and 23
studies [32,589 patients] describing the prevalence
of ABPA in CF) that have described the preva-
lence of AH and/or ABPA in patients with CF
(Table 9).
153,173,174,176200
A proportion metaanalysis of
these studies suggested the prevalence of AH in CF
of 34% (95% confidence interval, 27 to 41) and the
prevalence of ABPA of 7.8% (95% confidence inter-
val, 5.8 to 10) using a random effects model [Figs 6
and 7]. There was no uniformity in the diagnostic
criteria between different studies with varying crite-
ria used for diagnosis of AH and ABPA. This fact has
also been previously reported in a questionnaire-
based study, which revealed a considerable variabil-
ity in the criteria used for the diagnosis of ABPA in
CF.
201
Therefore, prospective reporting of cases with
uniform criteria would be the only way to reliably
identify the true prevalence of ABPA in CF.
Although a high proportion of CF patients develop
sensitization to A fumigatus, many demonstrate a
spontaneous decline in many immunologic parame-
ters, including IgE levels.
192
The diagnosis of ABPA
Figure 6. Proportion metaanalysis showing the prevalence of Aspergillus hypersensitivity in patients with cystic fibrosis (random effects
model).
in CF should not be based solely on serology and
skin test results, and prolonged testing might be
required to make a definite diagnosis (Table 10). The
treatment of ABPA in CF is not very different from
that of ABPA in bronchial asthma, except minimal
data are available to formulate conclusive treatment
recommendations for ABPA in CF. The treatment
issues are further complicated because pulmonary
exacerbations in a patient with ABPA and CF could
be related to ABPA or pulmonary infection, and
Figure 7. Proportion metaanalysis showing the prevalence of allergic bronchopulmonary aspergillosis in patients with CF (random
effects model).
818 Global Medicine
hence continuous assessment may be required over
months with repeat performance of all the serologic
investigations for ABPA before a decision to treat an
individual case is made.
202
ABPA Without Bronchial Asthma: ABPA may
occasionally develop in an individual without preex-
isting asthma. We have performed a systematic
MEDLINE search for the occurrence of ABPA
without bronchial asthma.
100
In total they included
36 cases reported across the globe; two cases dem-
onstrated bronchodilator reversibility,
203
and one
showed airway hyperresponsiveness to methacholine
challenge.
204
Most of the cases demonstrated hy-
persensitivity to A fumigatus, but three cases
showed hypersensitivity to Helminthosporium,
203
and one case each to Aspergillus niger.
205,206
Be-
cause of the absence of bronchial asthma, these
cases are often mistaken initially for other pulmo-
nary disorders like bronchogenic carcinoma
206208
or pulmonary tuberculosis.
100
ABPA Complicating Other Conditions: Occasion-
ally ABPA has been reported to complicate other
lung diseases like idiopathic bronchiectasis,
209
post-tubercular bronchiectasis,
210
bronchiectasis
secondary to Kartagener syndrome,
211
COPD,
212
and in patients with chronic granulomatous dis-
ease and hyper IgE syndrome.
213
However, these
are case reports or small case studies, and larger
observations are required to definitely establish an
association.
Coexistence of ABPA and Aspergilloma: The sero-
logic findings of ABPA have also been reported in
patients with aspergilloma
214224
and chronic necro-
tizing pulmonary aspergillosis.
225
This ABPA-like
syndrome probably represents a true hypersensitivity
reaction consequent to the colonization of Aspergil-
lus in long-standing pulmonary cavities and the
continuous release of Aspergillus antigens that leads
to immunologic activation.
214,215
Most patients show
a brisk response to glucocorticoids.
214217,224
Allergic Bronchopulmonary Mycosis: Allergic
bronchopulmonary mycosis is the occurrence of an
ABPA-like syndrome due to non-A fumigatus fungal
organisms. A variety of fungal agents (Table 11) have
been reported to cause this syndrome, but the fre-
quency is far less when compared to ABPA.
218,226240
ABPA and Allergic Aspergillus Sinusitis: Allergic
Aspergillus sinusitis (AAS) is a clinical entity in which
mucoid impaction akin to that of ABPA occurs in the
paranasal sinuses.
241
The pathogenesis is also similar
to ABPA and represents an allergic hypersensitivity
response to the presence of fungi within the sinus
cavity.
242
The patient is often asymptomatic or can
manifest with symptoms of nasal obstruction, rhinor-
Table 10Consensus Conference Proposed Diagnostic
and Screening Criteria for ABPA in CF
202
Classic diagnostic criteria
1. Acute or subacute clinical deterioration (cough, wheeze, and
other pulmonary symptoms) not explained by another etiology
2. Serum total IgE levels 1,000 IU/mL
3. Immediate cutaneous reactivity to Aspergillus or presence of
serum IgE antibody to A fumigatus
4. Precipitating antibodies to A fumigatus or serum IgG antibody
to A fumigatus
5. New or recent abnormalities on chest radiograph or chest CT
scan that have not cleared with antibiotics and standard
physiotherapy
Minimal diagnostic criteria
1. Acute or subacute clinical deterioration (cough, wheeze, and
other pulmonary symptoms) not explained by another etiology
2. Total serum IgE levels 500 IU/mL. If total IgE level is 200
500 IU/mL, repeat testing in 13 mo is recommended
3. Immediate cutaneous reactivity to Aspergillus or presence of
serum IgE antibody to A fumigatus
4. One of the following: (1) precipitins to A fumigatus or
demonstration of IgG antibody to A fumigatus; or (2) new or
recent abnormalities on chest radiography (on chest radiography
or chest CT scan that have not cleared with antibiotics and
standard physiotherapy)
Screening for ABPA in CF
1. Maintain a high level of suspicion for ABPA in patients with CF
2. Determine the total serum IgE levels annually. If the total
serum IgE levels is 500 IU/mL, perform A fumigatus skin test
or use an IgE antibody to A fumigatus. If results are positive,
consider diagnosis on the basis of minimal criteria
3. If the total serum IgE levels is 200500 IU/mL, repeat the
measurement if there is increased suspicion for ABPA and perform
further diagnostic tests (immediate skin test reactivity to A
fumigatus, IgE antibody to A fumigatus, A fumigatus precipitins, or
serum IgG antibody to A fumigatus, and chest radiography)
Table 11Fungi Implicated in the Causation of
Allergic Bronchopulmonary Mycosis
Fungi Study/Year
A niger Sharma et al
218
/1985
Helminthosporium spp Dolan et al
226
/1970
Penicillium spp Sahn and Lakshminarayan
227
/1973
Aspergillus ochraceus Novey and Wells
228
/1978
Stemphylium spp Benatar et al
229
/1980
Aspergillus terreus Laham et al
230
/1981
Drechslera spp McAleer et al
231
/1981
Torulopsis spp Patterson et al
232
/1982
Mucor-like spp Patterson et al
232
/1982
Candida spp Akiyama et al
234
/1984
Pseudallescheria spp Lake et al
235
/1990
Bipolaris spp Lake et al
236
/1991
Curvularia spp Lake et al
236
/1991
Schizophyllum spp Kamei et al
237
/1994
Fusarium spp Backman et al
238
/1995
Cladosporium spp Moreno-Ancillo et al
239
/1996
Saccharomyces spp Ogawa et al
240
/2004
rhea, headache, and epistaxis. Occasionally, the
allergic fungal sinusitis may extend into adjacent
spaces such as the orbit and manifest as propto-
sis.
243
Although in many patients with ABPA,
sinusitis can often be radiologically demonstrated,
it may not be possible to confirm the diagnosis of
AAS because many patients decline to undergo the
diagnostic procedures required to establish the
diagnosis. We currently label the patients with
ABPA as having concomitant AAS if there is
combination of hyperattenuating mucus and/or
bony erosion on a paranasal CT scan. Treatment is
initiated for ABPA with patients receiving addi-
tional intranasal glucocorticoids. If the symptoms
persist or are troublesome, surgical management
may be required for the management of AAS.
Conclusions
A high index of suspicion for ABPA should be
maintained while managing any patient with bron-
chial asthma whatever the severity or the level of
control. Host immunologic responses are central to
the pathogenesis, and they are the primary determi-
nants of the clinical, biologic, pathologic, and radio-
logic features of this disorder. ABPA may precede
the clinical recognition of the disorder for many
years or even decades, and it is often misdiagnosed as
a variety of pulmonary diseases. Because a patient
with ABPA can be minimally symptomatic or asymp-
tomatic, all patients with bronchial asthma should be
routinely screened with an Aspergillus skin test. In
patients with Aspergillus hypersensitivity, further
immunologic studies are warranted to diagnose
ABPA before the development of bronchiectasis
because bronchiectasis is a poor prognostic marker
in the natural history of this disease.
ACKNOWLEDGMENT: The author wishes to thank Dr. Aman-
jit Bal, Assistant Professor, Department of Histopathology,
PGIMER, Chandigarh for providing the histopathology photo-
graphs.
References
1 Bardana EJ Jr. The clinical spectrum of aspergillosispart
1: epidemiology, pathogenicity, infection in animals and
immunology of Aspergillus. Crit Rev Clin Lab Sci 1981;
13:2183
2 Geiser DM, Klich MA, Frisvad JC, et al. The current status
of species recognition and identification in Aspergillus. Stud
Mycol 2007; 59:110
3 Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of
aspergillosis: clinical practice guidelines of the infectious
diseases society of America. Clin Infect Dis 2008; 46:327
360
4 Soubani AO, Chandrasekar PH. The clinical spectrum of
pulmonary aspergillosis. Chest 2002; 121:19881999
5 Greenberger PA. Allergic bronchopulmonary aspergillo-
sis. J Allergy Clin Immunol 2002; 110:685692
6 Rosenberg M, Patterson R, Mintzer R, et al. Clinical and
immunologic criteria for the diagnosis of allergic broncho-
pulmonary aspergillosis. Ann Intern Med 1977; 86:405414
7 Greenberger PA, Patterson R, Ghory A, et al. Late sequelae
of allergic bronchopulmonary aspergillosis. J Allergy Clin
Immunol 1980; 66:327335
8 Patterson R, Greenberger PA, Radin RC, et al. Allergic
bronchopulmonary aspergillosis: staging as an aid to man-
agement. Ann Intern Med 1982; 96:286291
9 Patterson R, Greenberger PA, Halwig JM, et al. Allergic
bronchopulmonary aspergillosis: natural history and classifi-
cation of early disease by serologic and roentgenographic
studies. Arch Intern Med 1986; 146:916918
10 Patterson R, Greenberger PA, Lee TM, et al. Prolonged
evaluation of patients with corticosteroid-dependent asthma
stage of allergic bronchopulmonary aspergillosis. J Allergy
Clin Immunol 1987; 80:663668
11 Greenberger PA, Patterson R. Allergic bronchopulmonary
aspergillosis and the evaluation of the patient with asthma.
J Allergy Clin Immunol 1988; 81:646650
12 Greenberger PA, Miller TP, Roberts M, et al. Allergic
bronchopulmonary aspergillosis in patients with and without
evidence of bronchiectasis. Ann Allergy 1993; 70:333338
13 Greenberger PA. Clinical aspects of allergic bronchopulmo-
nary aspergillosis. Front Biosci 2003; 8:S119S127
14 Rajan TV. The Gell-Coombs classification of hypersensitivity
reactions: a re-interpretation. Trends Immunol 2003; 24:376
379
15 Geha RS, Sampson HA, Askenase PW, et al. Allergy and
hypersensitivity. In: Janeway CA, Travers P, Walport M, et al.
eds. Immunobiology. New York, NY: Garland, 2001; 517556
16 Hinson KFW, Moon AJ, Plummer NS. Broncho-pulmonary
aspergillosis; a review and a report of eight new cases.
Thorax 1952; 7:317333
17 Muscat I, Oxborrow S, Siddorn J. Allergic bronchopulmo-
nary mycosis. Lancet 1988; 1:1341
18 Kirsten D, Nowak D, Rabe KF, et al. [Diagnosis of bron-
chopulmonary aspergillosis is often made too late]. Med Klin
(Munich) 1993; 88:353356
19 Behera D, Guleria R, Jindal SK, et al. Allergic bronchopul-
monary aspergillosis: a retrospective study of 35 cases.
Indian J Chest Dis Allied Sci 1994; 36:173179
20 Al-Mobeireek AF, El-Rab M, Al-Hedaithy SS, et al. Allergic
bronchopulmonary mycosis in patients with asthma: period
prevalence at a university hospital in Saudi Arabia. Respir
Med 2001; 95:341347
21 Chakrabarti A, Sethi S, Raman DS, et al. Eight-year study of
allergic bronchopulmonary aspergillosis in an Indian teach-
ing hospital. Mycoses 2002; 45:295299
22 Agarwal R, Gupta D, Aggarwal AN, et al. Allergic broncho-
pulmonary aspergillosis: lessons from 126 patients attending
a chest clinic in North India. Chest 2006; 130:442448
23 Agarwal R, Gupta D, Aggarwal AN, et al. Clinical signifi-
cance of hyperattenuating mucoid impaction in allergic
bronchopulmonary aspergillosis: an analysis of 155 patients.
Chest 2007; 132:11831190
24 Agarwal R, Chakrabarti A. Epidemiology of allergic bron-
chopulmonary aspergillosis. In: Pasqualotto A, ed. As-
pergillosis: from diagnosis to prevention. New York, NY:
Springer, 2009 (in press)
25 Bateman ED. A new look at the natural history of Aspergil-
lus hypersensitivity in asthmatics. Respir Med 1994; 88:325
327
26 Malde B, Greenberger PA. Allergic bronchopulmonary as-
pergillosis. Allergy Asthma Proc 2004; 25:S38S39
820 Global Medicine
27 Tillie-Leblond I, Tonnel AB. Allergic bronchopulmonary
aspergillosis. Allergy 2005; 60:10041013
28 Donnelly SC, McLaughlin H, Bredin CP. Period prevalence
of allergic bronchopulmonary mycosis in a regional hospital
outpatient population in Ireland 198588. Ir J Med Sci
1991; 160:288290
29 Novey HS. Epidemiology of allergic bronchopulmonary
aspergillosis. Immunol Allergy Clin North Am 1998; 18:641
653
30 Agarwal R, Aggarwal AN, Gupta D, et al. Prevalence of
Aspergillus hypersensitivity and allergic bronchopulmonary
aspergillosis in patients with bronchial asthma: a systematic
review and meta-analysis. Int J Tuberc Lung Dis 2009 (in
press)
31 Attapattu MC. Allergic bronchopulmonary aspergillosis
among asthmatics. Ceylon Med J 1991; 36:4551
32 Schwartz HJ, Greenberger PA. The prevalence of allergic
bronchopulmonary aspergillosis in patients with asthma,
determined by serologic and radiologic criteria in patients at
risk. J Lab Clin Med 1991; 117:138142
33 Eaton T, Garrett J, Milne D, et al. Allergic bronchopulmo-
nary aspergillosis in the asthma clinic: a prospective evalu-
ation of CT in the diagnostic algorithm. Chest 2000; 118:
6672
34 Kumar R, Gaur SN. Prevalence of allergic bronchopulmo-
nary aspergillosis in patients with bronchial asthma. Asian
Pac J Allergy Immunol 2000; 18:181185
35 Maurya V, Gugnani HC, Sarma PU, et al. Sensitization to
Aspergillus antigens and occurrence of allergic bronchopul-
monary aspergillosis in patients with asthma. Chest 2005;
127:12521259
36 Prasad R, Garg R, Sanjay, et al. A study on prevalence of
allergic bronchopulmonary aspergillosis in patients of bron-
chial asthma. Internet J Pulmonary Med 2008; 9
37 Agarwal R, Nath A, Aggarwal AN, et al. Aspergillus hyper-
sensitivity and allergic bronchopulmonary aspergillosis in
patients with acute severe asthma in a respiratory ICU in
North India. Mycoses 2009 (in press)
38 Henderson AH. Allergic aspergillosis: review of 32 cases.
Thorax 1968; 23:513523
39 Kramer MN, Kurup VP, Fink JN. Allergic bronchopulmo-
nary aspergillosis from a contaminated dump site. Am Rev
Respir Dis 1989; 140:10861088
40 Kagen SL, Kurup VP, Sohnle PG, et al. Marijuana smoking
and fungal sensitization. J Allergy Clin Immunol 1983;
71:389393
41 Allmers H, Huber H, Baur X. Two year follow-up of a
garbage collector with allergic bronchopulmonary aspergil-
losis (ABPA). Am J Ind Med 2000; 37:438442
42 Chauhan B, Knutsen A, Hutcheson PS, et al. T cell subsets,
epitope mapping, and HLA-restriction in patients with
allergic bronchopulmonary aspergillosis. J Clin Invest 1996;
97:23242331
43 Miller PW, Hamosh A, Macek M Jr, et al. Cystic fibrosis
transmembrane conductance regulator (CFTR) gene muta-
tions in allergic bronchopulmonary aspergillosis. Am J Hum
Genet 1996; 59:4551
44 Aron Y, Bienvenu T, Hubert D, et al. HLA-DR polymor-
phism in allergic bronchopulmonary aspergillosis. J Allergy
Clin Immunol 1999; 104:891892
45 Chauhan B, Santiago L, Hutcheson PS, et al. Evidence for
the involvement of two different MHC class II regions in
susceptibility or protection in allergic bronchopulmonary
aspergillosis. J Allergy Clin Immunol 2000; 106:723729
46 Marchand E, Verellen-Dumoulin C, Mairesse M, et al. Fre-
quency of cystic fibrosis transmembrane conductance regulator
gene mutations and 5T allele in patients with allergic broncho-
pulmonary aspergillosis. Chest 2001; 119:762767
47 Eaton TE, Weiner Miller P, Garrett JE, et al. Cystic fibrosis
transmembrane conductance regulator gene mutations: do
they play a role in the aetiology of allergic bronchopulmo-
nary aspergillosis? Clin Exp Allergy 2002; 32:756761
48 Saxena S, Madan T, Shah A, et al. Association of polymor-
phisms in the collagen region of SP-A2 with increased levels
of total IgE antibodies and eosinophilia in patients with
allergic bronchopulmonary aspergillosis. J Allergy Clin Im-
munol 2003; 111:10011007
49 Brouard J, Knauer N, Boelle PY, et al. Influence of inter-
leukin-10 on Aspergillus fumigatus infection in patients with
cystic fibrosis. J Infect Dis 2005; 191:19881991
50 Knutsen AP. Genetic and respiratory tract risk factors for
aspergillosis: ABPA and asthma with fungal sensitization.
Med Mycol 2006; 44(suppl 1):6170
51 Knutsen AP, Kariuki B, Consolino JD, et al. IL-4 alpha chain
receptor (IL-4R) polymorphisms in allergic bronchopul-
monary aspergillosis. Clin Mol Allergy 2006; 4:3
52 Sambatakou H, Pravica V, Hutchinson IV, et al. Cytokine
profiling of pulmonary aspergillosis. Int J Immunogenet
2006; 33:297302
53 Vaid M, Kaur S, Sambatakou H, et al. Distinct alleles of
mannose-binding lectin (MBL) and surfactant proteins A
(SP-A) in patients with chronic cavitary pulmonary aspergil-
losis and allergic bronchopulmonary aspergillosis. Clin
Chem Lab Med 2007; 45:183186
54 Carvalho A, Pasqualotto AC, Pitzurra L, et al. Polymor-
phisms in toll-like receptor genes and susceptibility to
pulmonary aspergillosis. J Infect Dis 2008; 197:618621
55 Tomee JF, Wierenga AT, Hiemstra PS, et al. Proteases from
Aspergillus fumigatus induce release of proinflammatory
cytokines and cell detachment in airway epithelial cell lines.
J Infect Dis 1997; 176:300303
56 Tomee JF, Kauffman HF, Klimp AH, et al. Immunologic
significance of a collagen-derived culture filtrate containing
proteolytic activity in Aspergillus-related diseases. J Allergy
Clin Immunol 1994; 93:768778
57 Hogaboam CM, Blease K, Schuh JM. Cytokines and che-
mokines in allergic bronchopulmonary aspergillosis (ABPA)
and experimental Aspergillus-induced allergic airway or
asthmatic disease. Front Biosci 2003; 8:e147e156
58 Kauffman HF. Immunopathogenesis of allergic bronchopul-
monary aspergillosis and airway remodeling. Front Biosci
2003; 8:e190e196
59 Kauffman HK, Tomee JFC. Inflammatory cells and airway
defense against Aspergillus fumigatus. Immunol Allergy Clin
North Am 1998; 18:619640
60 Kauffman HF, Tomee JF, van de Riet MA, et al. Protease-
dependent activation of epithelial cells by fungal allergens
leads to morphologic changes and cytokine production.
61 Chauhan B, Santiago L, Kirschmann DA, et al. The
association of HLA-DR alleles and T cell activation with
allergic bronchopulmonary aspergillosis. J Immunol 1997;
159:40724076
62 Schuyler M. The Th1/Th2 paradigm in allergic bronchopul-
monary aspergillosis. J Lab Clin Med 1998; 131:194196
63 Knutsen AP, Bellone C, Kauffman H. Immunopathogenesis
of allergic bronchopulmonary aspergillosis in cystic fibrosis.
J Cyst Fibros 2002; 1:7689
64 Slavin RG, Bedrossian CW, Hutcheson PS, et al. A
pathologic study of allergic bronchopulmonary aspergil-
losis. J Allergy Clin Immunol 1988; 81:718725
65 Chan-Yeung M, Chase WH, Trapp W, et al. Allergic bron-
chopulmonary aspergillosis. Clinical and pathologic study of
three cases. Chest 1971; 59:3339
66 Riley DJ, Mackenzie JW, Uhlman WE, et al. Allergic
bronchopulmonary aspergillosis: evidence of limited tissue
invasion. Am Rev Respir Dis 1975; 111:232236
67 Case records of the Massachusetts General Hospital.
Weekly clinicopathological exercises. Case 242001. A 46-
year-old woman with chronic sinusitis, pulmonary nodules,
and hemoptysis. N Engl J Med 2001; 345:443449
68 Hanson G, Flor N, Wells I, et al. Bronchocentric granulo-
matosis: a complication of allergic bronchopulmonary as-
pergillosis. J Allergy Clin Immunol 1977; 59:8390
69 Kradin RL, Mark EJ. The pathology of pulmonary disorders
due to Aspergillus spp. Arch Pathol Lab Med 2008; 132:
606614
70 Starke ID, Keal EE. Cerebral aspergilloma in a patient with
allergic bronchopulmonary aspergillosis. Br J Dis Chest
1980; 74:301305
71 Bodey GP, Glann AS. Central nervous system aspergillosis
following steroidal therapy for allergic bronchopulmonary
aspergillosis. Chest 1993; 103:299301
72 Chung Y, Kraut JR, Stone AM, et al. Disseminated aspergil-
losis in a patient with cystic fibrosis and allergic broncho-
pulmonary aspergillosis. Pediatr Pulmonol 1994; 17:131134
73 Tsimikas S, Hollingsworth HM, Nash G. Aspergillus brain
abscess complicating allergic Aspergillus sinusitis. J Allergy
Clin Immunol 1994; 94:264267
74 Ganassini A, Cazzadori A. Invasive pulmonary aspergillosis
complicating allergic bronchopulmonary aspergillosis. Re-
spir Med 1995; 89:143145
75 Shah A, Kala J, Sahay S, et al. Frequency of familial occurrence
in 164 patients with allergic bronchopulmonary aspergillosis.
Ann Allergy Asthma Immunol 2008; 101:363369
76 Agarwal R, Singh N, Gupta D. Pulmonary hypertension as a
presenting manifestation of allergic bronchopulmonary as-
pergillosis. Indian J Chest Dis Allied Sci 2009; 51:3740
77 Ownby DR. Diagnostic tests in allergy. In: Lieberman P,
Anderson JA, eds. Allergic diseases: diagnosis and treatment.
Totowa, NJ: Humana Press, 2007; 2738
78 Malo JL, Paquin R. Incidence of immediate sensitivity to
Aspergillus fumigatus in a North American asthmatic pop-
ulation. Clin Allergy 1979; 9:377384
79 Ricketti AJ, Greenberger PA, Patterson R. Serum IgE as an
important aid in management of allergic bronchopulmonary
aspergillosis. J Allergy Clin Immunol 1984; 74:6871
80 Imbeau SA, Nichols D, Flaherty D, et al. Relationships
between prednisone therapy, disease activity, and the total
serum IgE level in allergic bronchopulmonary aspergillosis.
81 Leser C, Kauffman HF, Virchow C Sr, et al. Specific serum
immunopatterns in clinical phases of allergic bronchopulmo-
nary aspergillosis. J Allergy Clin Immunol 1992; 90:589599
82 Wang JL, Patterson R, Rosenberg M, et al. Serum IgE and
IgG antibody activity against Aspergillus fumigatus as a
diagnostic aid in allergic bronchopulmonary aspergillosis.
Am Rev Respir Dis 1978; 117:917927
83 McCarthy DS, Simon G, Hargreave FE. The radiological
appearances in allergic broncho-pulmonary aspergillosis.
Clin Radiol 1970; 21:366375
84 Mintzer RA, Rogers LF, Kruglik GD, et al. The spectrum of
radiologic findings in allergic bronchopulmonary aspergillo-
sis. Radiology 1978; 127:301307
85 Shah A, Panchal N, Agarwal AK. Allergic bronchopulmonary
aspergillosis: the spectrum of roentgenologic appearances.
Indian J Radiol Imaging 1999; 9:107112
86 Shah A. Allergic bronchopulmonary and sinus aspergillo-
sis: the roentgenologic spectrum. Front Biosci 2003; 8:
e138e146
87 Phelan MS, Kerr IH. Allergic broncho-pulmonary aspergil-
losis: the radiological appearance during long-term follow-
up. Clin Radiol 1984; 35:385392
88 Lynch DA. Imaging of asthma and allergic bronchopulmo-
nary mycosis. Radiol Clin North Am 1998; 36:129142
89 Panchal N, Bhagat R, Pant C, et al. Allergic bronchopulmo-
nary aspergillosis: the spectrum of computed tomography
appearances. Respir Med 1997; 91:213219
90 Goyal R, White CS, Templeton PA, et al. High attenuation
mucous plugs in allergic bronchopulmonary aspergillosis:
CT appearance. J Comput Assist Tomogr 1992; 16:649650
91 Logan PM, Muller NL. High-attenuation mucous plugging
in allergic bronchopulmonary aspergillosis. Can Assoc Ra-
diol J 1996; 47:374377
92 Karunaratne N, Baraket M, Lim S, et al. Case quiz: thoracic
CT illustrating hyperdense bronchial mucous plugging; al-
lergic bronchopulmonary aspergillosis. Australas Radiol
2003; 47:336338
93 Molinari M, Ruiu A, Biondi M, et al. Hyperdense mucoid
impaction in allergic bronchopulmonary aspergillosis: CT
appearance. Monaldi Arch Chest Dis 2004; 61:6264
94 Agarwal R, Aggarwal AN, Gupta D. High-attenuation mucus
in allergic bronchopulmonary aspergillosis: another cause of
diffuse high-attenuation pulmonary abnormality. AJR Am J
Roentgenol 2006; 186:904
95 Morozov A, Applegate KE, Brown S, et al. High-attenuation
mucus plugs on MDCT in a child with cystic fibrosis:
potential cause and differential diagnosis. Pediatr Radiol
2007; 37:592595
96 Scadding JG. The bronchi in allergic aspergillosis. Scand J
Respir Dis 1967; 48:372377
97 Neeld DA, Goodman LR, Gurney JW, et al. Computer-
ized tomography in the evaluation of allergic bronchopul-
monary aspergillosis. Am Rev Respir Dis 1990; 142:1200
1205
98 Angus RM, Davies ML, Cowan MD, et al. Computed
tomographic scanning of the lung in patients with allergic
bronchopulmonary aspergillosis and in asthmatic patients
with a positive skin test to Aspergillus fumigatus. Thorax
1994; 49:586589
99 Ward S, Heyneman L, Lee MJ, et al. Accuracy of CT in the
diagnosis of allergic bronchopulmonary aspergillosis in asth-
matic patients. AJR Am J Roentgenol 1999; 173:937942
100 Agarwal R, Aggarwal AN, Gupta D, et al. A rare cause of
miliary nodules: allergic bronchopulmonary aspergillosis.
BJR 2009 (in press)
101 Agarwal R, Reddy C, Gupta D. An unusual cause of hilar
lymphadenopathy. Lung India 2006; 23:9092
102 Shah A, Kala J, Sahay S. Allergic bronchopulmonary as-
pergillosis with hilar adenopathy in a 42-month-old boy.
Pediatr Pulmonol 2007; 42:747748
103 Murphy D, Lane DJ. Pleural effusion in allergic broncho-
pulmonary aspergillosis: two case reports. Br J Dis Chest
1981; 75:9195
104 OConnor TM, ODonnell A, Hurley M, et al. Allergic
bronchopulmonary aspergillosis: a rare cause of pleural
effusion. Respirology 2001; 6:361363
105 Ogasawara T, Iesato K, Okabe H, et al. A case of pleural
effusion associated with allergic bronchopulmonary aspergil-
losis during a relapse of the disease. Nihon Kokyuki Gakkai
Zasshi 2003; 41:905910
106 Cote CG, Cicchelli R, Hassoun PM. Hemoptysis and a lung
mass in a 51-year-old patient with asthma. Chest 1998;
114:14651468
107 Ko WK, Choi SW, Park JM, et al. A case of allergic
822 Global Medicine
bronchopulmonary aspergillosis shown as bilateral pulmo-
nary masses. Tuberc Respir Dis 1999; 46:260265
108 Otero Gonzalez I, Montero Martinez C, Blanco Aparicio M,
et al. Pseudotumoral allergic bronchopulmonary aspergillo-
sis. Arch Bronconeumol 2000; 36:351353
109 Sanchez-Alarcos JM, Martinez-Cruz R, Ortega L, et al.
ABPA mimicking bronchogenic cancer. Allergy 2001; 56:
8081
110 Coop C, England RW, Quinn JM. Allergic bronchopulmo-
nary aspergillosis masquerading as invasive pulmonary as-
pergillosis. Allergy Asthma Proc 2004; 25:263266
111 Agarwal R, Srinivas R, Aggarwal AN, et al. Pulmonary
masses in allergic bronchopulmonary aspergillosis: mecha-
nistic explanations. Respir Care 2008; 53:17441748
112 Longbottom JL, Pepys J. Pulmonary aspergillosis: diag-
nostic and immunological significance of antigens and
C-substance in Aspergillus fumigatus. J Pathol Bacteriol
1964; 88:141151
113 Vlahakis NE, Aksamit TR. Diagnosis and treatment of
allergic bronchopulmonary aspergillosis. Mayo Clin Proc
2001; 76:930938
114 Greenberger PA. Allergic bronchopulmonary aspergillo-
sis. J Allergy Clin Immunol 1984; 74:645653
115 Malo JL, Hawkins R, Pepys J. Studies in chronic allergic
bronchopulmonary aspergillosis: 1. Clinical and physiologi-
cal findings. Thorax 1977; 32:254261
116 McCarthy DS, Pepys J. Allergic broncho-pulmonary as-
pergillosis. Clinical immunology: 1. Clinical features. Clin
Allergy 1971; 1:261286
117 Nichols D, Dopico GA, Braun S, et al. Acute and chronic
pulmonary function changes in allergic bronchopulmonary
aspergillosis. Am J Med 1979; 67:631637
118 Kurup VP. Aspergillus antigens: which are important? Med
Mycol 2005; 43(suppl):S189S196
119 Kurup VP, Banerjee B, Hemmann S, et al. Selected recom-
binant Aspergillus fumigatus allergens bind specifically to
IgE in ABPA. Clin Exp Allergy 2000; 30:988993
120 Crameri R, Hemmann S, Ismail C, et al. Disease-specific
recombinant allergens for the diagnosis of allergic broncho-
pulmonary aspergillosis. Int Immunol 1998; 10:12111216
121 Crameri R. Recombinant Aspergillus fumigatus allergens:
from the nucleotide sequences to clinical applications. Int
Arch Allergy Immunol 1998; 115:99114
122 Crameri R, Lidholm J, Gronlund H, et al. Automated specific
IgE assay with recombinant allergens: evaluation of the recom-
binant Aspergillus fumigatus allergen I in the Pharmacia Cap
System. Clin Exp Allergy 1996; 26:14111419
123 Nikolaizik WH, Moser M, Crameri R, et al. Identification of
allergic bronchopulmonary aspergillosis in cystic fibrosis
patients by recombinant Aspergillus fumigatus I/a-specific
serology. Am J Respir Crit Care Med 1995; 152:634639
124 Hemmann S, Nikolaizik WH, Schoni MH, et al. Differential
IgE recognition of recombinant Aspergillus fumigatus aller-
gens by cystic fibrosis patients with allergic bronchopulmo-
nary aspergillosis or Aspergillus allergy. Eur J Immunol
1998; 28:11551160
125 Nikolaizik WH, Weichel M, Blaser K, et al. Intracutaneous
tests with recombinant allergens in cystic fibrosis patients
with allergic bronchopulmonary aspergillosis and Aspergillus
allergy. Am J Respir Crit Care Med 2002; 165:916921
126 Campbell MJ, Clayton YM. Bronchopulmonary aspergillo-
sis. A correlation of the clinical and laboratory findings in
272 patients investigated for bronchopulmonary aspergillo-
sis. Am Rev Respir Dis 1964; 89:186196
127 McCarthy DS, Pepys J. Allergic broncho-pulmonary as-
pergillosis: clinical immunology; 2. Skin, nasal and bronchial
tests. Clin Allergy 1971; 1:415432
128 Wang JL, Patterson R, Roberts M, et al. The management of
allergic bronchopulmonary aspergillosis. Am Rev Respir Dis
1979; 120:8792
129 Denning DW, ODriscoll BR, Hogaboam CM, et al. The
link between fungi and severe asthma: a summary of the
evidence. Eur Respir J 2006; 27:615626
130 Wark PA, Hensley MJ, Saltos N, et al. Anti-inflammatory
effect of itraconazole in stable allergic bronchopulmonary
aspergillosis: a randomized controlled trial. J Allergy Clin
Immunol 2003; 111:952957
131 Agarwal R, Chakrabarti A. Clinical features and natural
history of allergic bronchopulmonary aspergillosis. In: Pas-
qualotto A, ed. Aspergillosis: from diagnosis to prevention.
New York, NY: Springer, 2009 (in press)
132 Greenberger PA, Patterson R. Application of enzyme-linked
immunosorbent assay (ELISA) in diagnosis of allergic broncho-
pulmonary aspergillosis. J Lab Clin Med 1982; 99:288293
133 Rosenberg M, Patterson R, Roberts M, et al. The assess-
ment of immunologic and clinical changes occurring during
corticosteroid therapy for allergic bronchopulmonary as-
pergillosis. Am J Med 1978; 64:599606
134 Ricketti AJ, Greenberger PA, Patterson R. Varying presen-
tations of allergic bronchopulmonary aspergillosis. Int Arch
Allergy Appl Immunol 1984; 73:283285
135 Halwig JM, Greenberger PA, Levine M, et al. Recurrence of
allergic bronchopulmonary aspergillosis after seven years of
remission. J Allergy Clin Immunol 1984; 74:738740
136 Lee TM, Greenberger PA, Patterson R, et al. Stage V
(fibrotic) allergic bronchopulmonary aspergillosis: a review
of 17 cases followed from diagnosis. Arch Intern Med 1987;
147:319323
137 Patterson R. Allergic bronchopulmonary aspergillosis and
hypersensitivity reactions to fungi. In: Fishman AP, Elias JA,
Fishman JA, et al, eds. Fishmans pulmonary diseases and
disorders. New York, NY: McGraw-Hill, 1998; 777782
138 Baur X, Weiss W, Jarosch B, et al. Immunoprint pattern in
patients with allergic bronchopulmonary aspergillosis in
different stages. J Allergy Clin Immunol 1989; 83:839844
139 Kumar R, Chopra D. Evaluation of allergic bronchopulmo-
nary aspergillosis in patients with and without central bron-
chiectasis. J Asthma 2002; 39:473477
140 Kumar R. Mild, moderate, and severe forms of allergic
bronchopulmonary aspergillosis: a clinical and serologic
evaluation. Chest 2003; 124:890892
141 Denning DW, Van Wye JE, Lewiston NJ, et al. Adjunctive
therapy of allergic bronchopulmonary aspergillosis with
itraconazole. Chest 1991; 100:813819
142 Heinig JH, Weeke ER, Groth S, et al. High-dose local
steroid treatment in bronchopulmonary aspergillosis: a pilot
study. Allergy 1988; 43:2431
143 Balter MS, Rebuck AS. Treatment of allergic bronchopul-
monary aspergillosis with inhaled corticosteroids. Respir
Med 1992; 86:441442
144 Imbeault B, Cormier Y. Usefulness of inhaled high-dose
corticosteroids in allergic bronchopulmonary aspergillosis.
Chest 1993; 103:16141617
145 Seaton A, Seaton RA, Wightman AJ. Management of allergic
bronchopulmonary aspergillosis without maintenance oral
corticosteroids: a fifteen-year follow-up. QJM 1994; 87:529
537
146 Inhaled beclomethasone dipropionate in allergic broncho-
pulmonary aspergillosis: report to the Research Committee
of the British Thoracic Association. Br J Dis Chest 1979;
73:349356
147 Shale DJ, Faux JA, Lane DJ. Trial of ketoconazole in
non-invasive pulmonary aspergillosis. Thorax 1987;
42:2631
148 De Beule K, De Doncker P, Cauwenbergh G, et al. The
treatment of aspergillosis and aspergilloma with itracon-
azole, clinical results of an open international study (1982
1987). Mycoses 1988; 31:476485
149 Mannes GP, van der Heide S, van Aalderen WM, et al.
Itraconazole and allergic bronchopulmonary aspergillosis in
twin brothers with cystic fibrosis. Lancet 1993; 341:492
150 Pacheco A, Martin JA, Cuevas M. Serologic response to
itraconazole in allergic bronchopulmonary aspergillosis.
Chest 1993; 103:980981
151 Germaud P, Tuchais E. Allergic bronchopulmonary as-
pergillosis treated with itraconazole. Chest 1995; 107:883
152 Nikaido Y, Nagata N, Yamamoto T, et al. A case of allergic
bronchopulmonary aspergillosis successfully treated with
itraconazole. Respir Med 1998; 92:118119
153 Nepomuceno IB, Esrig S, Moss RB. Allergic bronchopul-
monary aspergillosis in cystic fibrosis: role of atopy and
response to itraconazole. Chest 1999; 115:364370
154 Salez F, Brichet A, Desurmont S, et al. Effects of itracon-
azole therapy in allergic bronchopulmonary aspergillosis.
Chest 1999; 116:16651668
155 Suzuki M, Sugiyama Y, Kitamura S. A case of allergic
bronchopulmonary aspergillosis refractory to the corticoste-
roid therapy and successfully treated by itraconazole. Japa-
nese J Chest Dis 1999; 58:770775
156 Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial
of itraconazole in allergic bronchopulmonary aspergillosis.
N Engl J Med 2000; 342:756762
157 Skov M, Hoiby N, Koch C. Itraconazole treatment of
allergic bronchopulmonary aspergillosis in patients with
cystic fibrosis. Allergy 2002; 57:723728
158 Kumar R, Singh P, Arora R, et al. Effect of itraconazole
therapy in allergic bronchopulmonary aspergillosis. Saudi
Med J 2003; 24:546547
159 Morimoto T, Ohnishi H, Fujiyama R, et al. Allergic bron-
chopulmonary aspergillosis successfully treated with itracon-
azole and fluticasone. Japanese J Chest Dis 2003; 62:5560
160 Ferrari M, Bodini I, Lo Cascio V. Rhabdomyolysis after the
administration of itraconazole to an asthmatic patient with
bronchopulmonary aspergillosis. Respiration 2004; 71:289291
161 Wark PA, Gibson PG, Wilson AJ. Azoles for allergic bron-
chopulmonary aspergillosis associated with asthma. Co-
chrane Database Syst Rev (database online). Issue 3, 2004
162 Tucker RM, Haq Y, Denning DW, et al. Adverse events
associated with itraconazole in 189 patients on chronic
therapy. J Antimicrob Chemother 1990; 26:561566
163 Lebrun-Vignes B, Archer VC, Diquet B, et al. Effect of
itraconazole on the pharmacokinetics of prednisolone and
methylprednisolone and cortisol secretion in healthy sub-
jects. Br J Clin Pharmacol 2001; 51:443450
164 Main KM, Skov M, Sillesen IB, et al. Cushings syndrome
due to pharmacological interaction in a cystic fibrosis pa-
tient. Acta Paediatr 2002; 91:10081011
165 Skov M, Main KM, Sillesen IB, et al. Iatrogenic adrenal
insufficiency as a side-effect of combined treatment of
itraconazole and budesonide. Eur Respir J 2002; 20:127133
166 Laoudi Y, Paolini JB, Grimfed A, et al. Nebulised cortico-
steroid and amphotericin B: an alternative treatment for
ABPA? Eur Respir J 2008; 31:908909
167 van der Ent CK, Hoekstra H, Rijkers GT. Successful
treatment of allergic bronchopulmonary aspergillosis with
recombinant anti-IgE antibody. Thorax 2007; 62:276277
168 Thomson JM, Wesley A, Byrnes CA, et al. Pulse intravenous
methylprednisolone for resistant allergic bronchopulmonary
aspergillosis in cystic fibrosis. Pediatr Pulmonol 2006; 41:
164170
169 Mulliez P, Croxo C, Roy-Saint Georges F, et al. Allergic
broncho-pulmonary aspergillosis treated with voriconazole.
Rev Mal Respir 2006; 23:9394
170 Bandres Gimeno R, Munoz Martinez MJ. Prolonged thera-
peutic response to voriconazole in a case of allergic bron-
chopulmonary aspergillosis. Arch Bronconeumol 2007; 43:
4951
171 Erwin GE, Fitzgerald JE. Case report: allergic bronchopul-
monary aspergillosis and allergic fungal sinusitis successfully
treated with voriconazole. J Asthma 2007; 44:891895
172 Mearns M, Young W, Batten J. Transient pulmonary infil-
trations in cystic fibrosis due to allergic aspergillosis. Thorax
1965; 20:385392
173 Kraemer R, Delosea N, Ballinari P, et al. Effect of allergic
bronchopulmonary aspergillosis on lung function in children
with cystic fibrosis. Am J Respir Crit Care Med 2006;
174:12111220
174 Mastella G, Rainisio M, Harms HK, et al. Allergic broncho-
pulmonary aspergillosis in cystic fibrosis: a European epide-
miological study; Epidemiologic Registry of Cystic Fibrosis.
Eur Respir J 2000; 16:464471
175 de Almeida MB, Bussamra MH, Rodrigues JC. Allergic
bronchopulmonary aspergillosis in paediatric cystic fibrosis
patients. Paediatr Respir Rev 2006; 7:6772
176 Knutsen AP, Hutcheson PS, Mueller KR, et al. Serum
immunoglobulins E and G anti-Aspergillus fumigatus anti-
body in patients with cystic fibrosis who have allergic
bronchopulmonary aspergillosis. J Lab Clin Med 1990;
116:724727
177 Laufer P, Fink JN, Bruns WT, et al. Allergic bronchopul-
monary aspergillosis in cystic fibrosis. J Allergy Clin Immu-
nol 1984; 73:4448
178 Mroueh S, Spock A. Allergic bronchopulmonary aspergillo-
sis in patients with cystic fibrosis. Chest 1994; 105:3236
179 Nicolai T, Arleth S, Spaeth A, et al. Correlation of IgE
antibody titer to Aspergillus fumigatus with decreased lung
function in cystic fibrosis. Pediatr Pulmonol 1990; 8:1215
180 Ritz N, Ammann RA, Casaulta Aebischer C, et al. Risk
factors for allergic bronchopulmonary aspergillosis and sen-
sitization to Aspergillus fumigatus in patients with cystic
fibrosis. Eur J Pediatr 2005; 164:577582
181 Becker JW, Burke W, McDonald G, et al. Prevalence of
allergic bronchopulmonary aspergillosis and atopy in adult
patients with cystic fibrosis. Chest 1996; 109:15361540
182 Geller DE, Kaplowitz H, Light MJ, et al. Allergic broncho-
pulmonary aspergillosis in cystic fibrosis: reported preva-
lence, regional distribution, and patient characteristics; Sci-
entific Advisory Group, Investigators, and Coordinators of
the Epidemiologic Study of Cystic Fibrosis. Chest 1999;
116:639646
183 Skov M, McKay K, Koch C, et al. Prevalence of allergic
bronchopulmonary aspergillosis in cystic fibrosis in an area
with a high frequency of atopy. Respir Med 2005; 99:887
893
184 Mearns M, Longbottom J, Batten J. Precipitating antibodies
to Aspergillus fumigatus in cystic fibrosis. Lancet 1967;
1:538539
185 Allan JD, Moss AD, Wallwork JC, et al. Immediate hyper-
sensitivity in patients with cystic fibrosis. Clin Allergy 1975;
5:255261
186 Silverman M, Hobbs FD, Gordon IR, et al. Cystic fibrosis,
atopy, and airways lability. Arch Dis Child 1978; 53:873877
187 Nelson LA, Callerame ML, Schwartz RH. Aspergillosis and
atopy in cystic fibrosis. Am Rev Respir Dis 1979; 120:863873
188 Feanny S, Forsyth S, Corey M, et al. Allergic bronchopulmo-
nary aspergillosis in cystic fibrosis: a secretory immune re-
sponse to a colonizing organism. Ann Allergy 1988; 60:6468
189 Schonheyder H, Jensen T, Hoiby N, et al. Clinical and
824 Global Medicine
serological survey of pulmonary aspergillosis in patients with
cystic fibrosis. Int Arch Allergy Appl Immunol 1988; 85:472
477
190 Zeaske R, Bruns WT, Fink JN, et al. Immune responses to
Aspergillus in cystic fibrosis. J Allergy Clin Immunol 1988;
82:7377
191 Simmonds EJ, Littlewood JM, Evans EG. Cystic fibrosis and
allergic bronchopulmonary aspergillosis. Arch Dis Child
1990; 65:507511
192 Hutcheson PS, Rejent AJ, Slavin RG. Variability in parameters
of allergic bronchopulmonary aspergillosis in patients with
cystic fibrosis. J Allergy Clin Immunol 1991; 88:390394
193 el-Dahr JM, Fink R, Selden R, et al. Development of
immune responses to Aspergillus at an early age in children
with cystic fibrosis. Am J Respir Crit Care Med 1994;
150:15131518
194 Marchant JL, Warner JO, Bush A. Rise in total IgE as an
indicator of allergic bronchopulmonary aspergillosis in cystic
fibrosis. Thorax 1994; 49:10021005
195 Hutcheson PS, Knutsen AP, Rejent AJ, et al. A 12-year
longitudinal study of Aspergillus sensitivity in patients with
cystic fibrosis. Chest 1996; 110:363366
196 Cimon B, Carrere J, Chazalette JP, et al. Bronchopulmonary
mycoses in cystic fibrosis: results of a five-year longitudinal
study. J Mycol Med 2000; 10:128135
197 Taccetti G, Procopio E, Marianelli L, et al. Allergic bron-
chopulmonary aspergillosis in Italian cystic fibrosis patients:
prevalence and percentage of positive tests in the employed
diagnostic criteria. Eur J Epidemiol 2000; 16:837842
198 Almeida MB, Bussamra MH, Rodrigues JC. ABPA diagnosis
in cystic fibrosis patients: the clinical utility of IgE specific to
recombinant Aspergillus fumigatus allergens. J Pediatr (Rio J)
2006; 82:215220
199 Chotirmall SH, Branagan P, Gunaratnam C, et al. Aspergil-
lus/allergic bronchopulmonary aspergillosis in an Irish cystic
fibrosis population: a diagnostically challenging entity. Re-
spir Care 2008; 53:10351041
200 Rapaka RR, Kolls JK. Pathogenesis of allergic bronchopul-
monary aspergillosis in cystic fibrosis: current understanding
and future directions. Med Mycol 2008; 17
201 Cunningham S, Madge SL, Dinwiddie R. Survey of criteria
used to diagnose allergic bronchopulmonary aspergillosis in
cystic fibrosis. Arch Dis Child 2001; 84:89
202 Stevens DA, Moss RB, Kurup VP, et al. Allergic broncho-
pulmonary aspergillosis in cystic fibrosis: state of the art;
Cystic Fibrosis Foundation Consensus Conference. Clin
Infect Dis 2003; 37(suppl):S225S264
203 Glancy JJ, Elder JL, McAleer R. Allergic bronchopulmonary
fungal disease without clinical asthma. Thorax 1981; 36:345
349
204 Yoshida N, Suguro H, Kohara F, et al. A case of allergic
bronchopulmonary aspergillosis with no history of bronchial
asthma. Nihon Kyobu Shikkan Gakkai Zasshi 1992; 30:2123
2127
205 Hoshino H, Tagaki S, Kon H, et al. Allergic bronchopulmo-
nary aspergillosis due to Aspergillus niger without bronchial
asthma. Respiration 1999; 66:369372
206 Shah A, Maurya V, Panjabi C, et al. Allergic bronchopulmo-
nary aspergillosis without clinical asthma caused by Aspergil-
lus niger. Allergy 2004; 59:236237
207 Berkin KE, Vernon DR, Kerr JW. Lung collapse caused by
allergic bronchopulmonary aspergillosis in non-asthmatic
patients. BMJ (Clin Res Ed) 1982; 285:552553
208 Bondue B, Remmelink M, Gevenois PA, et al. A pulmonary
cavitated mass complicating long-standing allergic broncho-
pulmonary aspergillosis. Respir Med Extra 2005; 1:3942
209 Bahous J, Malo JL, Paquin R, et al. Allergic bronchopulmo-
nary aspergillosis and sensitization to Aspergillus fumigatus
in chronic bronchiectasis in adults. Clin Allergy 1985;
15:571579
210 Agarwal R, Singh N, Aggarwal AN. An unusual association
between Mycobacterium tuberculosis and Aspergillus fu-
migatus. Monaldi Arch Chest Dis 2008; 69:3234
211 Sharma B, Sharma M, Bondi E. Kartageners syndrome
associated with allergic bronchopulmonary aspergillosis.
MedGenMed 2005; 7:25
212 Agarwal R, Srinivas R, Jindal SK. Allergic bronchopulmo-
nary aspergillosis complicating chronic obstructive pulmo-
nary disease. Mycoses 2008; 51:8385
213 Eppinger TM, Greenberger PA, White DA, et al. Sensitiza-
tion to Aspergillus species in the congenital neutrophil
disorders chronic granulomatous disease and hyper-IgE
syndrome. J Allergy Clin Immunol 1999; 104:12651272
214 Safirstein BH. Aspergilloma consequent to allergic bronchopul-
monary aspergillosis. Am Rev Respir Dis 1973; 108:940943
215 Ein ME, Wallace RJ Jr, Williams TW Jr. Allergic broncho-
pulmonary aspergillosis-like syndrome consequent to as-
pergilloma. Am Rev Respir Dis 1979; 119:811820
216 Israel RH, Poe RH, Bomba PA, et al. The rapid develop-
ment of an aspergilloma secondary to allergic bronchopul-
monary aspergillosis. Am J Med Sci 1980; 280:4144
217 Rosenberg IL, Greenberger PA. Allergic bronchopulmonary
aspergillosis and aspergilloma: long-term follow-up without
enlargement of a large multiloculated cavity. Chest 1984;
85:123125
218 Sharma TN, Gupta PR, Mehrotra AK, et al. Aspergilloma
with ABPA due to Aspergillus niger. J Assoc Physicians India
1985; 33:748
219 Shah A, Khan ZU, Chaturvedi S, et al. Allergic bronchopul-
monary aspergillosis with coexistent aspergilloma: a long-
term followup. J Asthma 1989; 26:109115
220 Bhagat R, Shah A, Jaggi OP, et al. Concomitant allergic
bronchopulmonary aspergillosis and allergic Aspergillus si-
nusitis with an operated aspergilloma. J Allergy Clin Immu-
nol 1993; 91:10941096
221 Shah A, Bhagat R, Pant K, et al. Allergic bronchopulmonary
aspergillosis with aspergilloma: exacerbation after prolonged
remission. Indian J Tuberc 1993; 40:3941
222 Jaques D, Bonzon M, Polla BS. Serological evidence of
Aspergillus type I hypersensitivity in a subgroup of pulmo-
nary aspergilloma patients. Int Arch Allergy Immunol 1995;
106:263270
223 Sharma P, Agarwal AK, Shah A. Formation of an aspergil-
loma in a patient with allergic bronchopulmonary aspergil-
losis on corticosteroid therapy. Indian J Chest Dis Allied Sci
1998; 40:269273
224 Shah A, Panjabi C. Contemporaneous occurrence of allergic
bronchopulmonary aspergillosis, allergic Aspergillus sinus-
itis, and aspergilloma. Ann Allergy Asthma Immunol 2006;
96:874878
225 Denning DW, Riniotis K, Dobrashian R, et al. Chronic
cavitary and fibrosing pulmonary and pleural aspergillosis:
case series, proposed nomenclature change, and review.
Clin Infect Dis 2003; 37(suppl):S265S280
226 Dolan CT, Weed LA, Dines DE. Bronchopulmonary hel-
minthosporiosis. Am J Clin Pathol 1970; 53:235242
227 Sahn SA, Lakshminarayan S. Allergic bronchopulmonary
penicilliosis. Chest 1973; 63:286288
228 Novey HS, Wells ID. Allergic bronchopulmonary aspergil-
losis caused by Aspergillus ochraceus. Am J Clin Pathol
1978; 70:840843
229 Benatar SR, Allan B, Hewitson RP, et al. Allergic broncho-
pulmonary stemphyliosis. Thorax 1980; 35:515518
230 Laham MN, Allen RC, Greene JC. Allergic bronchopulmo-
nary aspergillosis (ABPA) caused by Aspergillus terreus:
specific lymphocyte sensitization and antigen-directed se-
rum opsonic activity. Ann Allergy 1981; 46:7480
231 McAleer R, Kroenert DB, Elder JL, et al. Allergic broncho-
pulmonary disease caused by Curvularia lunata and Drech-
slera hawaiiensis. Thorax 1981; 36:338344
232 Patterson R, Samuels BS, Phair JJ, et al. Bronchopulmonary
torulopsosis. Int Arch Allergy Appl Immunol 1982; 69:3033
233 Kino T, Yamada Y, Honda K, et al. Diagnosis and treatment
of a case of allergic bronchopulmonary mycosis caused by
Mucor-like fungus. Nihon Kyobu Shikkan Gakkai Zasshi
1983; 21:896903
234 Akiyama K, Mathison DA, Riker JB, et al. Allergic broncho-
pulmonary candidiasis. Chest 1984; 85:699701
235 Lake FR, Tribe AE, McAleer R, et al. Mixed allergic
bronchopulmonary fungal disease due to Pseudallescheria
boydii and Aspergillus. Thorax 1990; 45:489491
236 Lake FR, Froudist JH, McAleer R, et al. Allergic broncho-
pulmonary fungal disease caused by Bipolaris and Curvu-
laria. Aust N Z J Med 1991; 21:871874
237 Kamei K, Unno H, Nagao K, et al. Allergic bronchopulmo-
nary mycosis caused by the basidiomycetous fungus Schizo-
phyllum commune. Clin Infect Dis 1994; 18:305309
238 Backman KS, Roberts M, Patterson R. Allergic bronchopul-
monary mycosis caused by Fusarium vasinfectum. Am J
Respir Crit Care Med 1995; 152:13791381
239 Moreno-Ancillo A, Diaz-Pena JM, Ferrer A, et al. Allergic
bronchopulmonary cladosporiosis in a child. J Allergy Clin
Immunol 1996; 97:714715
240 Ogawa H, Fujimura M, Tofuku Y. Allergic bronchopulmo-
nary fungal disease caused by Saccharomyces cerevisiae. J
Asthma 2004; 41:223228
241 Shah A, Panchal N, Agarwal AK. Concomitant allergic
bronchopulmonary aspergillosis and allergic Aspergillus si-
nusitis: a review of an uncommon association. Clin Exp
Allergy 2001; 31:18961905
242 Saravanan K, Panda NK, Chakrabarti A, et al. Allergic
fungal rhinosinusitis: an attempt to resolve the diagnostic
dilemma. Arch Otolaryngol Head Neck Surg 2006; 132:
173178
243 Shah TS, Sundaram P, Rege JD, et al. Proptosis in an
asthmatic patient. Postgrad Med J 2003; 79:710
826 Global Medicine

Chest: Allergic Bronchopulmonary Aspergillosis

Caricato da

Informazioni sul documento

Titolo originale

Copyright

Formati disponibili

Condividi questo documento

Condividi o incorpora il documento

Opzioni di condivisione

Hai trovato utile questo documento?

Questo contenuto è inappropriato?

Copyright:

Formati disponibili

Chest: Allergic Bronchopulmonary Aspergillosis

Caricato da

Copyright:

Formati disponibili

Allergic Bronchopulmonary

Potrebbero piacerti anche