Allergic Bronchopulmonary Aspergillosis Clinical Care Guidelines

Allergic bronchopulmonary aspergillosis is a hypersensitivity lung disease that results from exposure to Aspergillus fumigatus and occurs primarily in people with asthma or with cystic fibrosis. These guidelines were developed via a consensus conference of experts in 2003. 

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Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis Clinical Care Guidelines

Stevens DA, Moss RB, Kurup VP, Knutsen AP, Greenberger P, Judson MA, Denning DW, Crameri R, Brody AS, Light M, Skov M, Maish W, Mastella G, and participants in the Cystic Fibrosis Foundation Consensus Conference. Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis-State of the Art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis. 2003 Oct; 37 (Suppl 3), S225-64.PMID: 12975753

The 2003 recommendations addressed diagnostic criteria, screening, imaging, and treatment recommendations. Since 2003, there has been advancement in diagnostic ability via serology and immunologic testing. Most advancement has occurred in the treatment options. There has been more clarity in steroid dosing, but additional treatment options, including intravenous (IV) pulse steroids, systemic and inhaled antifungals, and anti-immunoglobulin E (IgE) therapy, have been explored. Future directions include the need for improved animal models as well as controlled treatment studies.

Purpose and Background

Allergic bronchopulmonary aspergillosis (ABPA), a lung disease of hypersensitivity to Aspergillus fumigatus (A. fumigatus) that primarily occurs in people with asthma or with cystic fibrosis, is seen in 2 to 19 percent of people with CF. People with CF may be predisposed to ABPA because of abnormal airway surface liquid and CF mucus. The disease is characterized by a variety of clinical and immunologic responses to A. fumigatus antigens. Clinical manifestations include:

  • Wheezing.
  • Pulmonary infiltrates (usually mucoid impaction).
  • Bronchiectasis.
  • Fibrosis.

The diagnosis of ABPA in people with CF is difficult and often delayed because of shared clinical features. ABPA has been associated with accelerated deterioration in lung disease, so timely diagnosis and treatment are imperative. 

Methodology

An expert panel was convened and a consensus conference held in 2001. The panel used the United States Preventive Services Task Force, 1989 grading methodology.

Recommendations

DIAGNOSIS: CLASSIC CASE

Recommendations Evaluation of the Evidence
1. Acute or subacute clinical deterioration (cough, wheeze, exercise intolerance, exercise-induced asthma, decline in pulmonary function, increased sputum) not attributable to another etiology. Consensus
2. Serum total IgE concentration of >1000 IU per mL unless patient is receiving systemic corticosteroids (if so, retest when steroid treatment is discontinued). Consensus
3. Immediate cutaneous reactivity to Aspergillus (prick skin test wheal of ≥3 mm in diameter with surrounding erythema, while the patient is not being treated with systemic antihistamines) or in vitro presence of serum IgE antibody to A. fumigatus. Consensus
4. Precipitating antibodies to A. fumigatus or serum IgG antibody to A. fumigatus by an in vitro test. Consensus
5. New or recent abnormalities on chest radiography (infiltrates or mucus plugging) or chest CT (bronchiectasis) that have not cleared with antibiotics and standard physiotherapy. Consensus

MINIMAL DIAGNOSTIC CRITERIA

Recommendations Evaluation of the Evidence
6. Acute or subacute clinical deterioration (cough, wheeze, exercise intolerance, exercise-induced asthma, change in pulmonary function, or increased sputum production) not attributed to another etiology. Consensus
7. Total serum IgE concentration of >500 IU per mL. If ABPA is suspected and the total IgE level is 200-500 IU per mL, repeat testing in one to three months is recommended. If patient is taking steroids, repeat when steroid treatment is discontinued. Consensus
8. Immediate cutaneous reactivity to Aspergillus (prick test wheal >3 mm with surrounding erythema, off systemic antihistamines) or in vitro demonstration of IgE antibody to A. fumigatus. Consensus
  1. 9. One of the following:
  2. Precipitins to A. fumigatus  or in vitro demonstration of IgG antibody to A. fumigatus.
  3. New or recent abnormalities on chest radiography (infiltrates or mucus plugging) or chest CT (bronchiectasis) that have not cleared with antibiotics and standard physiotherapy.
Consensus

SCREENING FOR ABPA

Recommendations Evaluation of the Evidence
10. Maintain a high level of suspicion for ABPA in patients >6 years of age. Consensus
11. Determine the total serum IgE concentration annually. If the total serum IgE concentration is >500 IU per mL, determine immediate cutaneous reactivity to A. fumigatus or use an in vitro test for IgE antibody to A. fumigatus. If results are positive, consider diagnosis on the basis of minimal criteria. Consensus
12. If the total serum IgE concentration is 200-500 IU per mL, repeat the measurement if there is increased suspicion for ABPA, such as by a disease exacerbation, and perform further diagnostic tests (immediate skin test reactivity to A. fumigatus, in vitro test for IgE antibody to A. fumigatus, A. fumigatus precipitins, or serum IgG antibody to A. fumigatus and chest radiography). Consensus

IMAGING

Recommendations Evaluation of the Evidence
13. Bronchiectasis
  1. Central predominance, common in ABPA without CF, is rare in CF.
  2. Lobar distribution of bronchiectasis is similar in both diseases.
  3. Central varicose bronchiectasis suggests ABPA.
  1. Grade II-2
  2. Grade II-2
  3. Grade III
14. Pulmonary infiltrates
  1. Infiltrates are common in both ABPA and CF.
  2. Infiltrates are more likely to partially or completely clear in response to steroids in ABPA, or CF with ABPA, than in CF without ABPA, although this response is variable.
  1. Grade III
  2. Grade III
15. Mucus plugging
  1. High attenuation mucus plugs have been reported in ABPA and not in CF.
  2. Mucus plugs are common in CF and in ABPA.
  3. Centrilobular nodules are seen in CF and in ABPA.
  1. Grade III
  2. Grade II-2
  3. Grade II-3
16. Pleural thickening
  1. Pleural thickening is seen in ABPA and in advanced CF.
Grade III
17. Imaging modality
  1. All imaging features described above are best identified with CT.
Grade III
TREATMENT  
Recommendations Evaluation of the Evidence
18. First line: systemic steroids -- prednisone 0.5-2.0 mg per kg per day, one to two weeks -- then attempt to taper within two to three months. Grade II-3
19. Second line: antifungal -- oral itraconazole 5 mg per kg per day (max 400 mg per day) for three to six months (if slow or poor response to steroids, relapse, or steroid toxicity).
  1. Therapeutic drug monitoring, liver function tests.
Grade III
20. Bronchodilators, inhaled steroids, antiasthma drugs only if indicated for asthma. Grade III

Unanswered Questions

New animal models are needed to better represent ABPA in CF. For example, Urb et al. developed a promising murine model for chronic Aspergillus airway infection (Infect Immun 2015, 83, 3590).

New and/or validated ways to better classify and distinguish Aspergillus lung phenotypes (i.e., colonization, infection/bronchitis, sensitization, and ABPA) are needed. For example, Baxter et al. added sputum Aspergillus PCR and galactomannan to standard serologic assays (J Allergy Clin Immunol 2013, 132, 560-6.e10). Gernez et al. showed diagnostic accuracy of basophil activation test (Eur Resp J 2016, 47, 177).

There is continued need for randomized placebo-controlled trials testing the efficacy of antifungals and Th2-directed biologics in people with ABPA CF.

Further Reading

Relevant manuscripts published after the original guidelines are listed below. These manuscripts have not been reviewed or endorsed by the guidelines committee.

Diagnostics

  • Tracy MC, Okorie CUA, Foley EA, Moss RB. Allergic Bronchopulmonary Aspergillosis. J. Fungi. 2016 Jun;2(2), 17.
  • Agarwal R, Chakrabarti A, Shah A, Gupta D, Meis JF, Guleria R, Moss R, Denning DW; ABPA complicating asthma ISHAM working group. Allergic bronchopulmonary aspergillosis: a review of literature and proposal of new diagnostic and classification criteria. Clin Exp Allergy. 2013 Aug;43(8):850-73. PMID: 23889240
  • Phuyal S, Garg MK, Agarwal R, Gupta P, Chakrabarti A, Sandhu MS, Khandelwal N. High-attenuation mucus impaction in patients with allergic bronchopulmonary aspergillosis: objective criteria on high-resolution computed tomography and correlation with serologic parameters. Curr Probl Diagn Radiol. 2016 May-Jun;45(3):168-73. Epub 2015 Aug 10. PMID: 26323654

Treatment

  • First-line treatment: Oral glucocorticosteroids: Agarwal R, Aggarwal AN, Dhooria S, Singh Sehgal I, Garg M, Saikia B, Behera D, Chakrabarti A. A randomised trial of glucocorticoids in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Eur Resp J. 2016 Feb;47(2):490-8. Epub 2015 Nov 19. PMID: 26585431
  • IV pulse glucocorticosteroids: Cohen-Cymberknoh M, Blau H, Shoseyov D, Mei-Zahav M, Efrati O, Armoni S, Kerem E. Intravenous monthly pulse methylprednisolone treatment for ABPA in patients with cystic fibrosis. J Cyst Fibros. 2009 Jul;8(4):253-7. Epub 2009 May 15. PMID: 19447081
  • Systemic antifungals: Elphick HE, Southern KW. Antifungal therapies for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database System Rev 2016, 11, CD002204. PMID: 27820955
  • Inhaled amphotericin: Ram B, Aggarwal AN, Dhooria S, Sehgal IS, Garg M, Behera D, Chakrabarti A, Agarwal R. A pilot randomized trial of nebulized amphotericin in patients with allergic bronchopulmonary aspergillosis. J Asthma. 2016 Jun;53(5):517-24. Epub 2016 Jan 22. PMID: 26666774
  • Omalizumab: Clinicaltrials.gov identifier NCT00787917- https://clinicaltrials.gov/ct2/show/NCT00787917
  • Omalizumab: Voskamp AL, Gillman A, Symons K, Sandrini A, Rolland JM, O'Hehir RE, Douglass JA. Clinical efficacy and immunologic effects of omalizumab in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol Pract. 2015 Mar-Apr;3(2):192-9. Epub 2015 Jan 29. PMID: 25640470
  • Omalizumab: Jat KR, Walia DK, Khairwa A. Anti-IgE therapy for allergic bronchopulmonary aspergillosis in people with cystic fibrosis. Cochrane Database System Rev. 2015 Nov 4;(11):CD010288. PMID: 26545165
  • Tompkins MG, Pettit R. Beyond the Guidelines: Treatment of Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis. Ann Pharmacother. 2022 Feb;56(2):181-192. doi: 10.1177/10600280211022065 Epub 2021 Jun
  • Eraso IC, Sangiovanni S, Morales EI, Fernández-Trujillo L. Use of monoclonal antibodies for allergic bronchopulmonary aspergillosis in patients with asthma and cystic fibrosis: literature review. Ther Adv Respir Dis. Jan-Dec 2020;14:1753466620961648. doi: 10.1177/1753466620961648. PMID: 33050821

This executive summary was prepared by:

Caroline Okorie, MD, MPH, and Richard B. Moss, MD, (Stanford University)

The guidelines were published in October 2003, they were reviewed in July 2021 and it was determined that no update is needed at this time.

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