3. Introduction
Aspergillosis of the respiratory tract has diverse manifestations that range from
hypersensitivity disorders to rapidly invasive disseminated disease
These can be classified into 3 distinct clinical categories:
> Allergic aspergillosis
> Saprophytic colonization
> Invasive aspergillosis
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
4. Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
5. Patterson K, et al. Allergic Bronchopulmonary Aspergillosis. PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY 2010.
6. Introduction
Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disorder caused by
hypersensitivity to Aspergillus fumigatus that complicates the course of patients with
asthma and cystic fibrosis
ABPA can rarely complicate other lung diseases like COPD, idiopathic bronchiectasis,
post-tubercular bronchiectasis, bronchiectasis secondary to Kartagener’s syndrome,
chronic granulomatous disease, hyper-IgE syndrome
In susceptible hosts, an allergic response is evoked by repeated inhalation of Aspergillus
spores
The fungal antigens elicit mainly a type I reaction (+/- type III and IV reactions), but tissue
invasion does not occur
When fungi other than Aspergillus are responsible for such a condition, it is termed as
allergic bronchopulmonary mycoses (ABPM)
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
8. Introduction
It presents with varied clinical and radiological manifestations:
> Uncontrolled asthma
> Recurrent pulmonary infiltrates
> Bronchiectasis (+/-)
The disease remains under-diagnosed in many countries:
> 33% misdiagnosed as pulmonary tuberculosis
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
9. Introduction
Aspergillosis-induced asthma (AIA) = patients with asthma who have a positive immediate
(type I) IgE-mediated hypersensitivity to Aspergillus
A wide variation to the tune of 16% to 38% has been observed in Aspergillus sensitization
among asthmatics across the world
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
10. Introduction
Severe asthma with fungal sensitization (SAFS) = a subset of asthmatics that demonstrated
sensitization to fungal antigens and had frequent exacerbations of asthma that
necessitated admission to the hospital
Diagnostic criteria:
> Severe (poorly controlled) asthma
> Either a positive skin prick test result for fungi (but not necessarily to Aspergillus species)
or in vitro demonstration of antifungal IgE of at least 0.4 kU/L
> Total serum IgE concentration <1,000 kU/L
Unlike in ABPA, patients with SAFS do not have mucoid impaction or bronchiectasis
While severe asthma is one of the diagnostic criteria for SAFS, ABPA also develops in those
with mild or moderate asthma
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
11. Epidemiology
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
Denning et al. estimated the global burden of 4.8 million (range 1.4–
6.8) ABPA patients in a world-wide asthma population of 193 million
13. Abbas AK, et al. Immunity to Microbes. CELLULAR AND MOLECULAR IMMUNOLOGY (9th EDITION) 2018.
14. Knutsen AP, et al. Allergic Bronchopulmonary Aspergillosis in Asthma and Cystic Fibrosis. Clinical and Developmental Immunology 2011.
15. Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
16. Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
17. Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
19. Diagnosis and Diagnostic Criteria:
Clinical Features
Symptoms Signs
Poorly controlled asthma Fever
Wheezing Wheezing
Hemoptysis Localized findings of consolidation and atelectasis
Productive cough
(Brownish black mucus plugs 31–69%)
Pulmonary hypertension
Low grade fever Clubbing
(Long-standing bronchiectasis)
Weight loss
Malaise and fatigue
Asymptomatic
(Diagnosed on routine investigations)
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
20.
21. Diagnosis and Diagnostic Criteria:
Diagnostic Tests
Roentgenologic manifestations
Eosinophil count
Skin testing with Aspergillus antigens
Total serum IgE
Specific IgE/IgG to A. fumigatus
Precipitating antibodies against A. fumigatus
Pulmonary function testing
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
22. Diagnosis and Diagnostic Criteria:
Diagnostic Tests > Roentgenologic Manifestations
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
23. Agarwal R, et al. Pictorial essay: Allergic bronchopulmonary aspergillosis. Indian Journal of Radiology and Imaging 2011.
24. Agarwal R, et al. Pictorial essay: Allergic bronchopulmonary aspergillosis. Indian Journal of Radiology and Imaging 2011.
25. Agarwal R, et al. Pictorial essay: Allergic bronchopulmonary aspergillosis. Indian Journal of Radiology and Imaging 2011.
26. Diagnosis and Diagnostic Criteria:
Diagnostic Tests > Eosinophil Count
During exacerbations, most patients have an absolute eosinophil count between 1,000
and 3,000 per cumm
While a normal eosinophil count may be seen in patients on treatment with corticosteroids
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
27. Diagnosis and Diagnostic Criteria:
Diagnostic Tests > Skin Testing with Aspergillus Antigens
Both type I (immediate) and type III (delayed) skin sensitivity with different Aspergillus
antigens can be found in patients with ABPA
The Aspergillus antigen extracts available are not uniform
The prick test is used for the initial screening of ABPA, if the prick test is negative, then
intradermal testing (More sensitive) can be performed
Up to 40% of all asthmatics and up to 56% of patients with CF are sensitized to Af:
> Recombinant Aspergillus fumigatus antigens
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
28. Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
29. Diagnosis and Diagnostic Criteria:
Diagnostic Tests > Total Serum IgE
There still remains a disagreement among different research groups in the cutoff level for
IgE:
> Rosenberg-Patterson criteria >> greater than 1,000 IU/mL (2,500 ng/mL)
> Minimal essential criteria >> greater than 417 IU/mL (1,000 ng/mL)
> ABPA in CF consensus criteria >> greater than 500 IU/mL (1250 ng/ml)
> ISHAM working group criteria >> greater than 1,000 IU/mL (2,500 ng/mL)
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
30. Diagnosis and Diagnostic Criteria:
Diagnostic Tests > Specific IgE/IgG to A. fumigatus
Generally, double the serum values of IgE-Af and IgG-Af are found in patients with ABPA
as compared to AIA
The ISHAM Working Group has suggested IgE-Af level >0.35 kUA/L to be diagnostic
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
31. Diagnosis and Diagnostic Criteria:
Diagnostic Tests > Precipitating Antibodies against A. fumigatus
By the double immunodiffusion technique of Outcherlony, precipitating antibodies against
Af could be detected in the unconcentrated serum from 70% of patients
Using concentrated serum, this detection rate improved to 92% of patients with a
radiological infiltrate
These precipitating antibodies have also been found in 10% of asthmatics without ABPA,
aspergilloma and in different forms of chronic pulmonary aspergillosis (CPA)
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
32. Diagnosis and Diagnostic Criteria:
Diagnostic Tests > Pulmonary Function Testing
Pulmonary function testing does not help confirm the diagnosis of ABPA
Acute or the exacerbation stage:
> Airflow obstruction
> Restrictive pattern with reduction in TLC, VC, FEV1, DLCO
After treatment with corticosteroids and during remission:
> Normalization of some of these parameters
Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
33. Hew M, et al. Allergic Bronchopulmonary Aspergillosis, Hypersensitivity Pneumonitis, and Epidemic Thunderstorm Asthma. Middleton's Allergy (9th Edition) 2019.
1977 1991 2013 2003
34. Shah A, et al. Allergic Bronchopulmonary Aspergillosis: A Perplexing Clinical Entity. Allergy Asthma Immunol Res 2016.
35. Patterson K, et al. Allergic Bronchopulmonary Aspergillosis. PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY 2010.
36. Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
37. Differential Diagnosis
Allergic bronchopulmonary aspergillosis/mycoses
Severe asthma with fungal sensitization
Allergic and non-allergic asthma
Bacterial/viral pneumonia
Pulmonary TB
Chronic eosinophilic pneumonia
Churg-Strauss vasculitis
Helminthic infections
Cystic fibrosis without ABPA
Medications/toxins: NSAIDs, antibiotics, organic chemicals
Hew M, et al. Allergic Bronchopulmonary Aspergillosis, Hypersensitivity Pneumonitis, and Epidemic Thunderstorm Asthma. Middleton's Allergy (9th Edition) 2019.
38. Staging
Hew M, et al. Allergic Bronchopulmonary Aspergillosis, Hypersensitivity Pneumonitis, and Epidemic Thunderstorm Asthma. Middleton's Allergy (9th Edition) 2019.
39. Staging
Hew M, et al. Allergic Bronchopulmonary Aspergillosis, Hypersensitivity Pneumonitis, and Epidemic Thunderstorm Asthma. Middleton's Allergy (9th Edition) 2019.
40. Management
Goals of therapy
Control of asthma
Prevention and treatment of acute exacerbations
Arresting the development of bronchiectasis and CPA
Suppression of the
immune activity:
systemic
glucocorticoids
Attenuation of
the fungal load in
the airways:
antifungal agents
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
41. Management
Systemic glucocorticoid therapy
Inhaled corticosteroids
Azoles
Biologic agents
Other Therapies
Follow-up
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
42. Management:
Systemic Glucocorticoid Therapy
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
Oral corticosteroids are currently the
treatment of choice for ABPA
There are no well-designed trials of steroids
in ABPA
The use of lower doses of glucocorticoids
without antifungal therapy is associated
with higher occurrence of recurrent
relapses or glucocorticoid dependence
(45%)
A higher dosage of glucocorticoids was
shown to be associated with higher
remission rates and a lower prevalence of
glucocorticoid-dependent ABPA (13.5%)
45. Management:
Inhaled Corticosteroids
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
46. Management:
Azoles
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
50% of patients relapse when systemic
corticosteroids are tapered and 20–45%
become glucocorticoid dependent
Many patients develop adverse effects
related to chronic steroid therapy
The use of specific antifungal agents in ABPA
can decrease the immune response by
reducing the antigenic stimulus consequent
to a decreased fungal burden
Azoles:
> Ketoconazole
> Itraconazole (Less toxic than
ketoconazole)
> Voriconazole/posaconazole (For
itraconazole failures)
> Amphotericin (Nebulized)
47. Randomized, double blind trial
Treatment with either 200 mg of itraconazole twice daily or placebo for 16 weeks in
patients who met immunologic and pulmonary-function criteria for corticosteroid-
dependent ABPA
Outcomes:
> A reduction of at least 50% in the corticosteroid dose
> A decrease of at least 25% in the serum IgE concentration
> One of the following: an improvement of at least 25% in exercise tolerance or PFTs or
resolution or absence of pulmonary infiltrates
> In a second, open-label part of the trial, all the patients received 200 mg of
itraconazole per day for 16 weeks
48. For patients with corticosteroid-dependent ABPA, the addition of itraconazole can lead to
improvement in the condition without added toxicity
49. Benitez LL, et al. Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents. Drugs 2019.
50. Benitez LL, et al. Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents. Drugs 2019.
53. Prednisolone was more effective in inducing response than itraconazole in acute-stage ABPA
Itraconazole was also effective in a considerable number and, with fewer side effects
compared with prednisolone, remains an attractive alternative in the initial treatment of ABPA
58. Management:
Other Therapies
Nebulized hypertonic saline (7%, 4–5 mL): reduce the viscosity of sputum to ease
expectoration of mucus plugs
Long-term azithromycin therapy: decrease cough and expectoration in patients with
bronchiectasis and frequent exacerbations
Therapeutic bronchoscopy: proximal collapse (Persists after 3–4 weeks of oral steroid
therapy)
Environmental control: gardening, agricultural and farm-related activities, exposure to
home or other building renovations, housing close to a composting site, cleaning old dusty
environments
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
59. Management:
Follow-Up
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.
60. Complications
Recurrent exacerbations: mucoid impaction, airflow limitation
Large airway collapse: acute hypoxemic respiratory failure
Bronchiectasis
Chronic pulmonary aspergillosis (CPA):
> Lobe shrinkage with fibrosis (40%)
> Pulmonary cavitation (3-21%)
> Pleural fibrosis (18-43%)
Cor pulmonale and/or type 2 respiratory failure: bronchiectasis, pulmonary fibrosis
Agarwal A, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria. Clinical & Experimental Allergy 2013.