ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS (ABPA)

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ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS(ABPA) A
N OVERVIEW DIAGNOSIS AND CLASSIFICATION

• By Dr.Amit Kumar

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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
hypersensitivity to the aspergillus fumigatus.
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
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What is Aspergillus?
Aspergillus is an ubiquitous, thermotolerant
mold. That reside in decaying organic matter.
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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.
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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.
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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.
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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.
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• CLINICAL PRESENTATION
• Common signs and symptoms
• Low grade fever
• Wheezing
• Bronchial hyperactivity
• Haemoptysis
• Productive cough (often associated with brownish
  black mucus plugs)

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• 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.

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• 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.

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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 patients 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 patients baseline IgE levels
  indicates relapse of ABPA.

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• 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

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• 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-in-bud opacities

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• 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 gt 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.

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• 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.

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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 (gt1,000 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)
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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

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Minimal diagnostic criteria for ABPA

• 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

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• 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 (gt1000 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

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Stage 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
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Stage III Exacerbation/recurrence Recurrence/wors
enning of clinical symptoms Recurrent pulmonary
infiltrates Rising IgE levels
Disease is characterized by the development of
new pulmonary infiltrates or by a gt100 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.
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• Stage - 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)

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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
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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.
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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 gt 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).
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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.
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Allergic Bronchopulmonary Mycosis Allergic
bronchopulmonary mycosis is the occurrence of an
ABPA-like 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.
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PROGNOSISWith 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,gt 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 lt0.8 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.
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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.
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