ABPA(Allergic Broncho

Pulmonary Aspergillosis)
DR LAVANYA S V
POST GRADUATE
DEPARTMENT OF PULMONARY MEDICINE
Contents
• Introduction
• Epidemiology
• Pathogenesis
• Pathology
• Clinical features
• Investigation
• Clinical and radiological classification
• Diagnostic criteria
• Treatment
• Differential diagnosis
• Complication
• Special Conditions
• Summary
INTRODUCTION:
• ABPA is a complex immunological pulmonary disorder caused by hypersensitivity to Aspergillus
fumigatus, with resultant systemic immune activation, chronic asthma, recurrent pulmonary
infiltrates and bronchiectasis.

• Allergic bronchopulmonary mycosis (ABPM) is an ABPA-like syndrome due to fungal organisms

other than A. fumigatus.

• ABPA complicates the course of diseases in patients with bronchial asthma and Cystic Fibrosis
Characteristics of ASPERGILLUS
• 250 species of Aspergillus.

• A. fumigatus, A. flavus, and A. niger – Most common

• Thermotolerant, Ubiquitous mold found in organic debris, dust, compost, foods, spices
and rotted plants

• Most common indoor molds (attics and basements, bedding, curtains, floor mats and
house dust)

• Cultured using Sabouraud’s agar medium at 37 C

 Simple colonization Aspergilloma

Hypersensitivity
pneumonitis

IgE dependent
ASPERGILLUS Asthma

ABPA

Chronic necrotising
pulmonary
aspergillosis
Invasive Aspergillosis
EPIDEMIOLOGY
• Aspergillus hypersensitivity (AH) is defined as the presence of an immediate-type cutaneous

hypersensitivity to commercial (or an indigenously prepared) extracts of Aspergillus or an

increase in Aspergillus specific IgE levels. First step in the development of ABPA.

• ABPA- Exaggerated form of AH

• ABPA - 1 to 2% in patients with bronchial asthma and 2 to 15% in patients with CF.

• Pooled prevalence of AH and ABPA of 28% and 12.9% respectively.

• In a recent study of 57 patients with severe acute asthma - prevalence of AH and ABPA of
around 51% and 39% respectively compared to the outpatient bronchial asthma
prevalence of 39% and 21% respectively
Pathogenesis of ABPA
• The spores of A. fumigatus (2 to 3.5 μm in size) are in the respirable range, and can thus
easily enter the airways

• In healthy individuals, Aspergillus is rapidly cleared by alveolar macrophages utilizing

oxidase-dependent killing mechanisms.
 Environmental factors + Genetic susceptibility

Inhaled conidia germinate -> hyphae in mucus plugs

• Presence of HLA DR-2 and

absence of HLA-DQ2 sequences
Fungi release antigens and exoproteases
• Garbage dump sites • Interleukin 10 promoter
• Agricultural conditions polymorphisms
• Bird droppings Compromise mucociliary clearance /Stimulate and • Surfactant protein A gene
• Smoking Moldy marijuana breach the airway epithelial barrier / Activate the polymorphisms
innate immune system of the lung • CFTR gene mutation
• Interleukin 15 polymorphisms
Influx of the inflammatory cells • Tumor necrosis factor-α
Early and late-phase inflammatory reactions polymorphisms
• Mannose-binding lectins
polymorphisms
APC present Ag to T cells ->activation of both Th1 and
Th2 responses • Interleukin 4 receptor
Release of IL-4, IL-5 and IL-13.
polymorphisms
• Interleukin 13 polymorphisms
Total and A. fumigatus-specific IgE synthesis, mast cell • Toll-like receptor gene
degranulation and promotion of a strong eosinophilic polymorphisms
response and tissue injury
Immunological Reactions:
• Immediate hypersensitivity (type I)

• Antigen-antibody complexes (type III)

• Eosinophil-rich inflammatory cell responses (type IVb)

 Diagnosis is primarily

Pathology based on the

serology and only a
minority of patients
requires lung biopsy

• Bronchiectasis involving segmental and subsegmental bronchi with sparing of distal bronchi

• Eosinophilic pneumonia

• Eosinophilic bronchitis

• Granulomatous bronchiolitis or bronchocentric granulomatosis

• Bronchiolitis obliterans with organizing pneumonia

• Localized tissue invasion by A. fumigatus without vascular invasion

• HPE: mucus, fibrin, Curschmann’s spirals, Charcot-Leyden crystals , inflammatory cells, Scanty
hyphae
Clinical Features:

HISTORY
• 3rd to 4th decade
• No gender predilection
• H/o Asthma poorly controlled with
PHYSICAL EXAMINATION:
drugs
• Wheeze- majority
• Low-grade fever, wheezing,
• Clubbing (16%)
bronchial hyperreactivity,
• Coarse crackles(15%)
hemoptysis or productive
• Bronchial breath sounds
cough(Expectoration of brownish
black mucus plugs )
• Weight loss and malaise
• Atopy with rhinitis, drug allergy,
and/or allergic conjunctivitis
Investigations
• Aspergillus Skin Test
• Total Serum Ig E levels
• Serum IgE and IgG antibodies specific to A. fumigatus
• Chest Xray
• HRCT Thorax
• Serum precipitins against A. fumigatus
• Peripheral eosinophilia
• Sputum cultures for A. fumigatus
• PFT
• Specific Aspergillus antigens
Aspergillus Skin Test
• Skin prick test/ Intradermal test

• Positive reaction - wheal and erythema within 1 minute

reaches a maximum after 10 to 20 minutes

and resolves within 1 to 2 hours.

• Positive in all ABPA

• Also positive in 40% of Asthma patients without ABPA

• Intradermal test more sensitive than SPT

Total Serum IgE levels
• Used for diagnosis and follow-up of ABPA

• Cut-off value - 1000 IU/mL

• After treatment with glucocorticoids, the serum IgE level starts declining

• 25 to 35% decline in IgE levels is taken as criteria for remission.

• Doubling of baseline IgE level signifies relapse

Peripheral eosinophilia
• AEC> 1000 cells/microliter- major criteria

• Low eosinophil count does not exclude the diagnosis of ABPA(53%)

Serum IgE and IgG ab specific to A.
fumigatus
• Hallmark of disease

• Measured by fluorescent enzyme immunoassay tests

• Cut-off value of IgG/IgE more than twice the pooled serum samples from patients with

Aspergillus-hypersensitive asthma can help in the diagnosis of ABPA

• Cut-off of 0.35 kUA per liter of A. fumigatus specific IgE- ABPA

Other tests
Serum precipitins against A. fumigatus

• Precipitating IgG ab are elicited from crude extracts of A. fumigatus

• Present in almost 85% of the patients with ABPA.

• Present in 1 to 10% of other subjects, hence supportive,not diagnostic.

Sputum cultures

• Supportive, but not diagnostic of ABPA

PFT

• No diagnostic value in ABPA, but help in categorizing the severity of asthma

Chest X Ray:
Transient
• Patchy areas of consolidation
• Radiologic infiltrates: ‘toothpaste and gloved finger’ shadows due to mucoid impaction in
dilated bronchi
• Collapse: lobar or segmental
• 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 effusion
Permanent
Parallel-line shadows representing bronchial widening
Ring-shadows 1–2 cm in diameter representing dilated bronchi en face
Pulmonary fibrosis
Cavitation
Pleural thickening
Mycetoma formation
Linear scars
Agarwal R, Khan A, Garg M, Aggarwal AN, Gupta D. Pictorial essay: Allergic bronchopulmonary aspergillosis. The Indian journal of radiology & imaging. 2011 Oct;21(4):242.
Agarwal R, Khan A, Garg M, Aggarwal AN, Gupta D. Pictorial essay: Allergic bronchopulmonary aspergillosis. The Indian journal of radiology & imaging. 2011 Oct;21(4):242.
Agarwal R, Khan A, Garg M, Aggarwal AN, Gupta D. Pictorial essay: Allergic bronchopulmonary aspergillosis. The Indian journal of radiology & imaging. 2011 Oct;21(4):242.
Agarwal R, Khan A, Garg M, Aggarwal AN, Gupta D. Pictorial essay: Allergic bronchopulmonary aspergillosis. The Indian journal of radiology & imaging. 2011 Oct;21(4):242.
Fleeting opacities

Agarwal R, Khan A, Garg M, Aggarwal AN, Gupta D. Pictorial essay: Allergic bronchopulmonary aspergillosis. The Indian journal of radiology & imaging. 2011 Oct;21(4):242.
CT THORAX
• 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
• High-attenuation mucus
• Pleural involvement-thickening/fibrosis
Central bronchiectasis
Mucus impaction
Centrilobular nodules:
Bronchiectasis with pneumothorax
Bronchiectasis with fibrosis
Aspergilloma
Clinical staging of ABPA - PATTERSON
Radiological classification of ABPA

1. GREENBERGER Classification

2. KUMAR Classification

3. AGARWAL Classification
GREENBERGER Classification

ABPA –S
(Seropositive ABPA)

ABPA ABPA- CB
(ABPA with Central
bronchiectasis)
KUMAR Classification

ABPA-S

ABPA
ABPA -CB

ABPA-CB –ORF
(ABPA-CB Other Radiological
Findings)
AGARWAL Classification

ABPA-S

ABPA
ABPA-CB

ABPA-CB-HAM
(high attenuation mucus)
Rosenberg – Patterson criteria of ABPA
Major criteria Minor criteria
• A Asthma • Expectoration of brownish-black mucus plugs
• R Roentgenographic fleeting pulmonary • Delayed cutaneous hypersensitivity to
opacities Aspergillus antigen
• T Skin test positive for Aspergillus (type I • Presence of Aspergillus in sputum
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
The presence of six out eight major criteria makes the diagnosis almost certain.
AGARWAL criteria for ABPA:
Predisposing conditions
• Bronchial asthma
• Cystic fibrosis
• Chronic obstructive pulmonary disease
• Others (hyper-IgE syndrome, chronic granulomatous disease, Kartagener's syndrome)
Obligatory criteria
• Elevated total IgE levels
• Elevated IgE and/or IgG levels against A. fumigatus
Other criteria (at least three of five)
• Immediate cutaneous hypersensitivity to Aspergillus antigen
• Presence of serum precipitating antibodies against A. fumigatus
• Radiographic pulmonary opacities (fixed/transient)
• AEC> 1000 cells per microliter
• Central bronchiectasis on HRCT
ISHAM criteria
• Obligatory critera(both should be present)

• Total IgE>1000IU/ml

• +ve Aspergillus specific(Af) IgE or skin prick test

• Other criteria(2 out of 3)

• Raised Af IgG or precipitins

• Eosinophils>500 cells/uL

• Radiological features consistent with ABPA

Severe Asthma With Fungal Sensitivity
(SAFS)
• Antifungal therapies are effective in patients with poorly controlled asthma that have
some of the criteria for ABPA-S, but do not reach the threshold for diagnosis - SAFS.

• SAFS typically have normal radiographic studies and a milder immunologic response
identified in patients with milder asthma.

• Difficult to differentiate from ABPA-S

Criteria for the Diagnosis of SAFS

1. History of poorly controlled asthma (>500 μg/d of fluticasone or the equivalent, near
continuous oral corticosteroids for >6 months , or >2 oral steroid tapers per year)

2. Total serum IgE <1000 IU/mL

3. Positive immediate skin test reactivity to Aspergillus fumigatus OR elevated specific

serum IgE to A. fumigatus

4. Absence of serum precipitins (by gel diffusion) and elevated specific serum IgG to A.
fumigatus

5. No radiographic evidence of bronchiectasis or infiltrates

Differential Diagnosis of ABPA:
• Steroid-dependent asthma without ABPA
• SAFS
• Chronic obstructive pulmonary disease (COPD)
• Chronic necrotizing aspergillosis
• Tuberculosis
• Parasitic infections
• Hypersensitivity pneumonitis
• Churg–Strauss syndrome
• Acute eosinophilic pneumonia (including drug-induced pneumonitis)
• Chronic eosinophilic pneumonia
• Lymphoma
• Idiopathic hypereosinophilic syndrome
• Autoimmune disease
Treatment Approach:
• Controlling the immune response (which is what makes the patient symptomatic)

• Decreasing the burden of organisms so that there is less of an immune response.

TREATMENT
1. Systemic corticosteroids

2. Inhaled corticosteroids

3. Oral Itraconazole

4. Other therapies
Systemic CORTICOSTEROIDS
• Treatment of choice for ABPA.

• Suppress the immune hyperfunction & acts as anti-inflammatory

• Different regimens available

Systemic CORTICOSTEROIDS

Regime 1 Regime 2
• Prednisolone 0.5 mg/kg/d for 1–2 weeks, • Prednisolone 0.75 mg/kg for 6 weeks, 0.5
then on alternate days for 6–8 weeks. mg/kg for 6 weeks

• Then taper by 5–10 mg every 2 week and • Taper by 5 mg every 6 week to continue for

discontinue a total duration of at least 6 to 12 months.

• Repeat the total serum IgE concentration • The total IgE levels are repeated every 6 to

and chest radiograph in 6 to 8 weeks 8 weeks for 1 year to determine the

baseline IgE concentrations
• Lower dose of glucocorticoids (regime 1 ) -frequent relapses or corticosteroid
dependence .

• Higher dose of glucocorticoids for a longer duration (regime 2 )-higher remission rates
and lower prevalence of glucocorticoid-dependent ABPA (13.5%).

• 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.
Follow-up and monitoring
• The patients are followed up with

1. Medical history and physical examination

2. Chest radiograph(Yearly)

3. Total IgE levels (every 2 months)

• A >35 % decline in IgE level signifies satisfactory response to therapy.

• Doubling of the baseline IgE value can signify a silent ABPA exacerbation
Inhaled corticosteroids
• Used only for the control of asthma, once the oral prednisolone dose is reduced to below 10
mg/day
Oral Anti-Fungals :
• The current concept is that ABPA is not a classic “infection”

• Presumably antifungals minimizes the degree of fungal colonization.

• Agents used : Itraconazole,Voriconazole , Ketaconazole(used initially)

Indications:
• Unable to taper oral glucocorticoids or have an exacerbation of ABPA
• Initial therapy for acute ABPA
Itraconazole
Dose: 200 mg three times a day for three days, then 200 mg twice a day for 16 weeks then
once a day for 16 weeks.

Indications: -

• First relapse of ABPA or -

• Glucocorticoid-dependent ABPA
Itraconazole
• Significant reductions in corticosteroid dose, decreased IgE levels, greater resolution of
pulmonary infiltrates, and gains in exercise tolerance or pulmonary function

• Adverse effects - 39% of patients.

• Numerous drug interactions(cyclosporine, oral hypoglycemics, tacrolimus, terfenadine,

cisapride, midazolam)

• Adrenal insufficiency
Other therapy

• Inhaled amphotericin and budesonide.

• Omalizumab (biologic- Anti-IgE antibody)

• Pulse doses of IV methylprednisolone.

• Methotrexate (as steroid-sparing agent in patients with steroid-dependent ABPA/ in

steroids contra indicated patients)

• Airway clearance techniques

• Avoid environmental exposure , use of HEPA filters.

Complications
• Recurrent asthma exacerbations

• Bronchiectasis

• Pulmonary hypertension

• Type 2 respiratory failure

• Secondary amyloidosis
Special conditions
ABPA without Bronchial Asthma
• 36 cases reported across the globe

• Because of the absence of bronchial asthma, these cases are often mistaken initially for
bronchogenic carcinoma or PTB
ABPA in Cystic Fibrosis
• Key element in the immunopathogenesis -exposure of the bronchial lymphoid tissue to
high levels of Aspergillus allergens because of abnormal mucus properties resulting from
the CFTR conductance regulator mutations.

• ABPA characteristics similar to poorly controlled CF .

• The prevalence of AH in CF- 29% to 53%, ABPA in CF is 1 to 15%.

• Higher rates of microbial colonization, pneumothorax, massive hemoptysis and poorer

nutritional status
ABPA and Aspergilloma
• Serological findings of ABPA has also been reported in patients with aspergilloma and
chronic necrotizing pulmonary aspergillosis(ABPA like syndrome)

• Continuous release of Aspergillus antigens->immunologic activation in a genetically

predisposed individual
Allergic Bronchopulmonary Mycosis
• ABPA-like syndrome due to non-Aspergillus fumigatus fungal organisms

• Aspergillus niger
• Helminthosporium spp
• Penicillium spp
• Aspergillus ochraceus
• Stemphylium spp
• Aspergillus terreus
• Drechslera spp
• Torulopsis spp
• Mucor-like spp
• Candida spp
• Pseudallescheria spp
• Bipolaris spp
• Curvularia spp
• Schizophyllum spp
• Fusarium spp
• Cladosporium spp Saccharomyces spp
ABPA and other conditions
• Idiopathic bronchiectasis
• Post-tubercular bronchiectasis
• Bronchiectasis secondary to Kartagener’s syndrome
• COPD
• Chronic granulomatous disease
• Hyper IgE syndrome
Sinobronchial Allergic Mycosis (SAM)
Syndrome
• Concomitant Allergic fungal sinusitis and ABPM represents an expression of the same
process of fungal hypersensitivity involving the upper and lower airways.

• Allergic Aspergillus Sinusitis (AAS)- mucoid impaction in paranasal sinus.

• Symptoms - nasal obstruction, rhinorrhea, headache and epistaxis

• Additional intranasal glucocorticoids.

• Spread to adjacent spaces(proptosis), intracranial extradural spread

SUMMARY
• Hypersensitivity to Aspergillus fumigatus

• Complicates the course of bronchial asthma and Cystic Fibrosis

• C/F: Low-grade fever, wheezing, brownish mucus plugs, fever

• Investigations: Aspergillus skin test, Serum Ig E, CXR, HRCT thorax, eosinophilia, ab against
aspergillus.

• Diagnostic criteria: Rosenberg- Patterson criteria

• Treatment:Systemic corticosteroids,Inhaled corticosteroids,Oral Itraconazole,Other therapies

REFERENCES
1. FISHMAN’S Pulmonary diseases and disorders- 5th Edition

2. Textbook of pulmonary and critical care medicine-S.K.JINDAL- 2nd Edition

3. Agarwal R, Khan A, Garg M, Aggarwal AN, Gupta D. Pictorial essay: Allergic

bronchopulmonary aspergillosis. The Indian journal of radiology & imaging. 2011

Oct;21(4):242.

4. Shah A, Panjabi C. Allergic aspergillosis of the respiratory tract.

5. Patterson K, Strek ME. Allergic bronchopulmonary aspergillosis. Proceedings of

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