Allergic bronchopulmonary aspergillosis

Allergic Bronchopulmonary Aspergillosis
Pairach Supsongserm
Allergy and Clinical Immunology Fellow
King Chulalongkorn Memorial Hospital
24 July 2020

Outline
 Introduction
 Epidemiology
 Pathogenesis
 Diagnosis and diagnostic criteria
 Differential diagnosis
 Staging
 Management
 Complications
 Questions

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.

Patterson K, et al. Allergic Bronchopulmonary Aspergillosis. PROCEEDINGS OF THE AMERICAN THORACIC SOCIETY 2010.

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.

Greenberger PA, et al. Allergic Bronchopulmonary Aspergillosis. J ALLERGY CLIN IMMUNOL PRACT 2014.

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

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

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

Epidemiology
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

Abbas AK, et al. Immunity to Microbes. CELLULAR AND MOLECULAR IMMUNOLOGY (9th EDITION) 2018.

Knutsen AP, et al. Allergic Bronchopulmonary Aspergillosis in Asthma and Cystic Fibrosis. Clinical and Developmental Immunology 2011.

Diagnosis
and
Diagnostic Criteria

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)

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

Diagnostic Tests > Roentgenologic Manifestations

Agarwal R, et al. Pictorial essay: Allergic bronchopulmonary aspergillosis. Indian Journal of Radiology and Imaging 2011.

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

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

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)

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

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)

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

Hew M, et al. Allergic Bronchopulmonary Aspergillosis, Hypersensitivity Pneumonitis, and Epidemic Thunderstorm Asthma. Middleton's Allergy (9th Edition) 2019.
1977 1991 2013 2003

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

Staging

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

Management
 Systemic glucocorticoid therapy
 Inhaled corticosteroids
 Azoles
 Biologic agents
 Other Therapies
 Follow-up

Management:
Systemic Glucocorticoid Therapy
 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%)

Medium-dose oral glucocorticoids are as effective and
safer than high-dose in treatment of ABPA

Management:
Inhaled Corticosteroids

Management:
Azoles
 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)

 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

For patients with corticosteroid-dependent ABPA, the addition of itraconazole can lead to
improvement in the condition without added toxicity

Benitez LL, et al. Adverse Effects Associated with Long-Term Administration of Azole Antifungal Agents. Drugs 2019.

Glucocorticoid VS Azoles in ABPA ???

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

Management:
Biologic Agents
 Anti-IgE biologics: omalizumab
 Anti-IL-5 biologics: mepolizumab (Case report)

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

Management:
Follow-Up

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

Allergic bronchopulmonary aspergillosis

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