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Allergic Bronchopulmonary Aspergillosis
Allergic Bronchopulmonary Aspergillosis
ICD-9
518.6
OMIM
103920
DiseasesDB
956
MedlinePlus
000070
eMedicine
radio/55
MeSH
D001229
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Pathophysiology
Aspergillus spores are small (23 m in diameter) and can penetrate deep into the respiratory system to the alveolar
level. In healthy people, innate and adaptive immune responses are triggered by various immune cells (notably
neutrophils, resident alveolar macrophages and dendritic cells) drawn to the site of infection by numerous
inflammatory cytokines and neutrophilic attractants (such as CXCR2 receptor ligands). In this situation, mucociliary
clearance is initiated and spores are successfully phagocytosed, clearing the infection from the host.
In people with predisposing lung diseasessuch as persistent asthma or cystic fibrosis (or rarer diseases such as
chronic granulomatous disease or Hyper-IgE syndrome)several factors lead to an increased risk of ABPA. These
include immune factors (such as atopy or immunogenic HLA-restricted phenotypes), as well as genetic factors (such
as CFTR gene mutations in both asthmatics and cystic fibrosis patients). By allowing Aspergillus spores to persist in
Diagnosis
The exact criteria for the diagnosis of ABPA are not yet universally agreed upon, though working groups have
proposed specific guidelines.
ABPA should be suspected in patients with a predisposing lung diseasemost commonly asthma or cystic
fibrosispresenting with symptoms of recurrent infection such as fever, but who do not respond to conventional
antibiotic therapy. Poorly-controlled asthma is a common finding, with a case series only finding 19% of ABPA
patients with well-controlled asthma. Wheezing and hemoptysis (coughing up blood) are common features, and
mucus plugging is seen in 3169% of patients.
Radiological investigation
Consolidation and mucoid impaction are the most commonly described radiological features described in ABPA
literature, though much of the evidence for consolidation comes from before the development of computed
tomography (CT) scans. Tramline shadowing, finger-in-glove opacities and toothpaste shadows are also prevalent
findings.
When utilising high resolution CT scans, there can be better assessment of the distribution and pattern of
bronchiectasis within the lungs, and hence this is the tool of choice in the radiological diagnosis of ABPA. Central
(confined to medial two-thirds of medial half of the lung) bronchiectasis that peripherally tapers bronchi is
considered a requirement for ABPA pathophysiology, though in up to 43% of cases there is considerable extension
to the periphery of the lung.
Mucoid impaction of the upper and lower airways is a common finding. Plugs are hypodense but appear on CT with
high attenuation in up to 20% of patients. Where present it is a strong diagnostic factor of ABPA and distinguishes
symptoms from other causes of bronchiectasis.
CT scans may more rarely reveal mosaic-appearance attenuation, centrilobular nodules, tree-in-bud opacities and
pleuropulmonary fibrosis (a finding consistent with CPA, a disease with ABPA as a known precursor). Rarely other
manifestations can be seen on CT scans, including military nodular opacities, perihilar opacities (that mimic hilar
lymphadenopathy), pleural effusions and pulmonary masses. Cavitation and aspergilloma are rarer findings, not
exceeding 20% of patients, and likely represent a shift from ABPA to CPA if accompanied by pleural thickening or
fibrocavitary disease.
Culture
Culturing fungi from sputum is a supportive test in the diagnosis of ABPA, but is not 100% specific for ABPA as A.
fumigatus is ubiquitous and commonly isolated from lung expectorant in other diseases. Nevertheless, between
4060% of patients do have positive cultures depending on the number of samples taken.
Staging
New criteria by the ABPA Complicated Asthma ISHAM Working Group suggests a 6-stage criteria for the diagnosis
of ABPA, though this is yet to be formalised into official guidelines. This would replace the current gold standard
staging protocol devised by Patterson and colleagues. Stage 0 would represent an asymptomatic form of ABPA, with
controlled asthma but still fulfilling the fundamental diagnostic requirements of a positive skin test with elevated
total IgE (>1000 IU/mL). Stage 6 is an advanced ABPA, with the presence of type II respiratory failure or
pulmonary heart disease, with radiological evidence of severe fibrosis consistent with ABPA on a high-resolution
CT scan. It must be diagnosed after excluding the other, reversible causes of acute respiratory failure.
Treatment
Underlying disease must be controlled to prevent exacerbation and worsening of ABPA, and in most patients this
consists of managing their asthma or CF. Any other co-morbidities, such as sinusitis or rhinitis, should also be
addressed.
Hypersensitivity mechanisms, as described above, contribute to progression of the disease over time and, when left
untreated, result in extensive fibrosis of lung tissue. In order to reduce this, corticosteroid therapy is the mainstay of
treatment (for example with prednisone); however, studies involving corticosteroids in ABPA are limited by small
cohorts and are often not double-blinded. Despite this, there is evidence that acute-onset ABPA is improved by
corticosteroid treatment as it reduces episodes of consolidation. There are challenges involved in long-term therapy
with corticosteroidswhich can induce severe immune dysfunction when used chronically, as well as metabolic
disordersand approaches have been developed to manage ABPA alongside potential adverse effects from
corticosteroids.
The most commonly described technique, known as sparing, involves using an antifungal agent to clear spores from
airways adjacent to corticosteroid therapy. The antifungal aspect aims to reduce fungal causes of bronchial
inflammation, whilst also minimising the dose of corticosteroid required to reduce the immune systems input to
disease progression. The strongest evidence (double-blinded, randomized, placebo-controlled trials) is for
itraconazole twice daily for four months, which resulted in significant clinical improvement compared to placebo,
and was mirrored in CF patients. Using itraconazole appears to outweigh the risk from long-term and high-dose
prednisone. Newer triazole drugssuch as posaconazole or voriconazolehave not yet been studied in-depth
through clinical trials in this context.
Whilst the benefits of using corticosteroids in the short term are notable, and improve quality of life scores, there are
cases of ABPA converting to invasive aspergillosis whilst undergoing corticosteroid treatment. Furthermore, in
concurrent use with itraconazole, there is potential for drug interaction and the induction of Cushing syndrome in
rare instances. Metabolic disorders, such as diabetes mellitus and osteoporosis, can also be induced.
In order to mitigate these risks, corticosteroid doses are decreased biweekly assuming no further progression of
disease after each reduction. When no exacerbations from the disease are seen within three months after
discontinuing corticosteroids, the patient is considered to be in complete remission. The exception to this rule is
patients who are diagnosed with advanced ABPA; in this case removing corticosteroids almost always results in
exacerbation and these patients are continued on low-dose corticosteroids (preferably on an alternate-day schedule).
Serum IgE can be used to guide treatment, and levels are checked every 68 week after steroid treatment
commences, followed by every 8 weeks for one year. This allows for determination of baseline IgE levels, though
its important to note that most patients do not entirely reduce IgE levels to baseline. Chest X-ray or CT scans are
performed after 12 months of treatment to ensure infiltrates are resolving.
Epidemiology
There are limited national and international studies into the burden of ABPA, made more difficult by a
non-standardized diagnostic criteria. Estimates of between 0.53.5% have been made for ABPA burden in asthma,
and 115% in CF. Five national cohorts, detecting ABPA prevalence in asthma (based on GINA estimates), were
used in a recent meta-analysis to produce an estimate of the global burden of ABPA complicating asthma. From 193
million asthma sufferers worldwide, ABPA prevalence in asthma is estimated between the extremes of 1.356.77
million sufferers, using 0.73.5% attrition rates. A compromise at 2.5% attrition has also been proposed, placing
global burden at around 4.8 million people affected. The Eastern Mediterranean region had the lowest estimated
prevalence, with a predicted case burden of 351,000; collectively, the Americas had the highest predicted burden at
1,461,000 cases. These are likely underestimates of total prevalence, given the exclusion of CF patients and children
from the study, as well as diagnostic testing being limited in less developed regions.
References
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[4]
[5]
[6]
External links
The Fungal Research Trust (http://www.fungalresearchtrust.org) funded Aspergillus Website (http://www.
aspergillus.org.uk) provides patient support at Aspergillosis Patients Support Website (http://www.aspergillus.
org.uk/newpatients) and a highly active support group at Aspergillus Support (http://uk.groups.yahoo.com/
group/AspergillusSupport/).
Allergic Bronchopulmonary Aspergillosis (http://www.gpnotebook.co.uk/simplepage.cfm?ID=1100611584)
GP Notebook
Allergic Bronchopulmonary Aspergillosis (http://www.merckmanuals.com/home/lung_and_airway_disorders/
allergic_and_autoimmune_diseases_of_the_lungs/allergic_bronchopulmonary_aspergillosis.html) The Merck
Manuals Online Medical Library
Medpix. ABPA radiology pictures (http://rad.usuhs.mil/medpix/medpix.html?mode=caption_search&
srchstr=allergic+bronchopulmonary+aspergillosis#top/)
The Aspergillus Website Treatment Section. (http://www.aspergillus.org.uk/secure/treatmentindex/index.
php)
Aspergillus (http://www.aspergillus.org.uk/) Aspergillus Website (Diagnosis, Treatment, Cases, Images,
Educational video)
Aspergillus Patients Support (http://www.aspergillus.org.uk/patients/New/welcomepages.php)
Aspergillus Patients (Questions & Answers, Support Group)
License
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