By Dr.Amit Kumar
What is ABPA?
ABPA is an idiopathic inflammatory lung disease characterized by an
allergic inflammatory response to the colonization of aspergillus fumigatus.
In another way “ABPA is an immunologic pulmonary disorder
caused
by
fumigatus.
hypersensitivity
to
the
aspergillus
“
It was first described in 1952 by Hinson and coworkers and then again in
1967, when Scadding recognized an association of this disease with proximal
bronchiectasis in areas previously affected by infiltrates
(predominantly in the upper lobes). The first adult case of ABPA in the
United States was described in 1968
What is Aspergillus?
Aspergillus is an ubiquitous, thermotolerant mold. That reside in
decaying organic matter.
There are approximately 250 species of Aspergillus, but only a
few are human pathogens. Depending on the host immunity
and the organism virulence, the respiratory disease caused by
aspergillus are aspergilloma, allergic aspergillus sinusitits,
ABPA, hypersensitivity pneumonias, airway invasive
aspergillosis, chronic necrotizing pulmonary aspergillosis and
invasive aspergillosis.
The spectrum of disease is broad and can be severe and
debilitating, requiring lung transplantation, however if
recognized early and managed aggressively, ABPA is treatable
can remit indefinitely and progressive lung damage can be
avoided.
Epidemiology
There is no gender predilection and majority of the
cases present in the third to fifth decade of life but may also
present during childhood.
The prevalence of ABPA is about 1-2% in asthma
patients and 2-15% in cystic fibrosis patients.
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 wide spread availability of serologic assays.
In a recent meta analysis a prevalence of aspergillus
hypersensitivity and ABPA in asthma of 28% and 12.9%
respectively.
Pathogenesis of ABPA
Although the pathogenesis of ABPA is incompletely
understood, it is believed to result from a complex
immunological reaction to chronic airway colonization by
aspergillus. Inhaled spores colonize the airway, proliferate and
result in chronic antigenic stimulation of the airway, tissue
injury and the clinical features of ABPA.
At the microscopic level ABPA is characterized by an
intense eosinophilic and mononuclear cell inflammatory
response that leads to airway injury and bronchiectasis.
A role for type I hypersensitivity reactions is strongly
suggested by the elevated serum levels of total and
Aspergillus-specific IgE.
Type III hypersensitivity is suggested by the presence of
Aspergillus ,precipitins and circulating immune complexes
during disease exacerbations.
A type IV cell-mediated immune reaction may also be at
work, based on the finding of dual (immediate and delayed)
cutaneous reactions and in vitro lymphocyte transformation to
Aspergillus antigen stimulation in some patients.
CLINICAL PRESENTATION
Common signs and symptoms
•Low grade fever
•Wheezing
•Bronchial hyperactivity
•Haemoptysis
•Productive cough (often associated with brownish black
mucus plugs)
PHYSICAL EXAMINATION
•Can be normal
•Other possible findings include :
Polyphonic wheezing
Clubbing (16%)
Coarse crackles (15%)
Sign and symptoms of pulmonary HTN and/or
respiratory failure.
•During exacerbations of ABPA, localized findings of
consolidation and atelectasis can occur.
 LABORATORY FINDINGS
 Aspergillus Skin Test: The
Aspergillus skin test is performed
using an A fumigatus antigen. 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
significance remains unclear.
Total Serum IgE
Levels
 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 patient’s current symptoms.
The only situation where IgE levels 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 conducted.
After treatment with glucocorticoids, the serum
IgE levels decline, and a 35 to 50% decrease is
taken as a criteria for remission. The serum IgE
determination is also used for follow-up, and a
doubling of the patient’s baseline IgE levels
indicates relapse of ABPA.
 Serum IgE and IgG Antibodies Specific to A
fumigates :
An elevated level of A fumigatus-specific
antibodies measured by fluorescent enzyme
immunoassay is considered the hallmark of
ABPA. 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
 Radiologic Investigations:
A wide spectrum of radiographic appearances can occur
in ABPA. The chest radiographic findings of ABPA include
transient or fixed pulmonary opacities, tramline shadows,
finger-in-glove opacities, and toothpaste shadows.
Findings noted on high-resolution CT (HRCT) include
central bronchiectasis, mucoid impaction, mosaic
attenuation, presence of centrilobular nodules, and tree-inbud opacities
 Serum Precipitins Against A fumigatus: They
can also be present in other pulmonary disorders
and thus represent supportive not diagnostic
evidence for ABPA.
 Peripheral Eosinophilia: A blood absolute
eosinophil count > 1,000 cells/L is also a major
criterion for the diagnosis of ABPA. 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
diagnostic of ABPA.
 Pulmonary Function Tests: These tests help
categorize the severity of the lung disease but have
no diagnostic value in ABPA
 Role 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 and in patients with CF 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
Criteria Used for the Diagnosis of ABPA
Rosenberg-Patterson criteria
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
1. Presence of Aspergillus in sputum
2. Expectoration of brownish black mucus plugs
3. 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
1.
2.
3.
4.
5.
1.
2.
3.
4.
5.
Minimal ABPA-CB ( Central Bronchiectasis)
Asthma
Immediate cutaneous hyperreactivity to Aspergillus antigens
Central bronchiectasis
Elevated IgE
Raised A fumigatus-specific IgG and IgE
Minimal ABPA-S (Serum)
Asthma
Immediate cutaneous hyperreactivity to Aspergillus antigens
Transient pulmonary infiltrates on chest radiograph
Elevated IgE
Raised A fumigatus-specific IgG and IgE
STAGING OF ABPA:
ABPA has been classified into five stages, but a patient does
not necessarily progress from one stage to the other
sequentially.
Stage - I :
Acute phase
•Acute asthma symptoms, fever, weight loss.
•Elevated serum IgE (>1000 IU/ml)
•Peripheral blood eosinophilia (may be absent in
patients treated with oral coricosteroids)
•Fleeting infiltrates on chest x-ray (may be absent in
patients treated with oral coricosteroids)
•Positive specific IgE, IgG, skin test reactivity, and
precipitins to A. fumigatus
•Responds to steroids/antifungal therapy
Stage – II :
Remission
Asymptomatic
Generally normal or significant resolution of
radiologic opacities from the acute phase
Usually 35–50% 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
Stage III: Exacerbation/recurrence
Recurrence/worsenning of clinical symptoms
Recurrent pulmonary infiltrates
Rising IgE levels
Disease is characterized by the development of new pulmonary
infiltrates or by a >100 percent increase in total IgE.
Elevation of IgE may precede clinical or radiological worsening
during this stage, and an isolated increase in severity of
bronchospasm does not constitute an exacerbation. Although a
majority of disease exacerbations are associated with a
concomitant increase in symptoms, exacerbations may occur in
the absence of any increase in symptoms.
Stage - IV :
Glucocorticoid-dependent ABPA
•Symptomatic
Transient or fixed pulmonary opacities
oTwo 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)
Stage - 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
Differential Diagnosis and Complication
The disorder needs to be differentiated from the following conditions:
Aspergillus hypersensitive bronchial asthma,
Pulmonary tuberculosis in endemic areas,
Community-acquired pneumonia (especially acute presentations),
and other inflammatory pulmonary disorders such as eosinophilic
pneumonia,Bronchocentric Granulomatosis, and Churg-Strauss
syndrome.
The complications of ABPA include 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 screening 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. The occurrence of ABPA in CF is associated with
deterioration of lung function, higher rates of microbial colonization,
pneumothorax, massive hemoptysis, and poorer nutritional status.
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 200–500 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).
ABPA Complicating Other Conditions:
Occasionally ABPA has been reported to complicate other lung
diseases like idiopathic bronchiectasis, post-tubercular bronchiectasis,
bronchiectasis secondary to Kartagener syndrome, COPD, and in
patients with chronic granulomatous disease and hyper IgE syndrome.
Coexistence of ABPA and Aspergilloma:
The serologic findings of ABPA have also been reported in patients
with aspergilloma and chronic necrotizing pulmonary aspergillosis.
ABPA without Bronchial Asthma:
ABPA may occasionaly develop in an individual without pre existing
asthma.
Allergic Bronchopulmonary Mycosis:
Allergic bronchopulmonary mycosis is the occurrence of an ABPAlike syndrome due to non-A fumigatus fungal organisms.
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.
PROGNOSIS:
With appropriate treatment long-term control of ABPA is feasible, and durable
remissions are common.
Treatment of stage I disease with corticosteroids typically results in decreased sputum
production, improved control of bronchospasm,> 35 percent reduction in total IgE
within 8weeks, clearing of precipitating antibodies, and resolution of radiographic
infiltrates. IgE levels typically do not completely normalize but rather decrease by
approximately one-half of peak levels seen in the acute stage.
Progression of stage IV disease to pulmonary fibrosis can be prevented if patients are
maintained on low-dose steroids, and most patients with stage V disease have a
stable course over several years. Persons with an FEV1 persistently <0.8 L have a
worse prognosis.
In addition to severe airflow obstruction and pulmonary fibrosis, longterm
complications of ABPA occasionally include the development of an aspergilloma ,
chronic or recurrent lobar atelectasis, allergic Aspergillus sinusitis, or Aspergillus tissue
invasion and semi-invasive Aspergillosis.
Transplantation has been undertaken successfully among patients with ABPA,
however, post-transplant recurrence ofABPA has beenreported.
CONCLUSIONS
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. Host immunologic responses are central to
the pathogenesis, and they are the primary determinants of the
clinical, biologic, pathologic, and radiologic 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 asymptomatic, 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.