Allergic bronchopulmonary aspergillosis Presented by Athit Wutthisanwatthana, MD. August24, 2018

1. Allergic Bronchopulmonary Aspergillosis

2. Spectrum of Disease
• Upper respiratory tract
• Allergic aspergillosis
• Allergic Aspergillus sinusitis
• Saprophytic colonization
• Sinus fungal balls
• Invasive disease
• Acute fulminant invasive sinusitis
• Chronic invasive sinusitis
• Granulomatous invasive sinusitis

3. Spectrum of Disease
• Lower respiratory tract
• Allergic aspergillosis
• (IgE medidated) Aspergillus induced asthma
• Allergic bronchopulmonary aspergillosis
• Hypersensity pneumonitis
• Saprophytic colonization
• Aspergilloma
• Simple
• Complex (chronic cavitary pulmonary aspergillosis
• Invasive disease
• Invasive pulmonary aspergillosis
• Acute
• Subacute (chronic necrotizing pulmonary aspergillosis)

4. • Endotype of asthma
• An immunologically mediated disease
• Most commonly seen in asthma and cystic fibrosis (CF)
• Hypersensitivity to Aspergillus Ag
• Allergic bronchopulmonary mycoses (ABPM)

5. Severe asthma with fungal sensitization
• SAFS
• Severe (poorly controlled) asthma
• Positive skin test to fungi or anti fungal IgE >=0.4 kU/L
• Total IgE <1,000 kU/L

6. Epidemiology

7. Epidemiology
• Seen in 20s or 30s
• Reported in children and infants
• No gender predilection
• Asthma
• Denning (2013) 2.5%
• Asthma with positive skin test
• Greenberger and Patterson (1988) 6%
• Shah A (2014) 25-37%
• Cystic fibrosis
• Cystic Fibrosis Foundation (2003) 2-15%

8. Epidemiology
• International Society for Human and Animal Mycology (ISHAM)
• Working Group on ABPA complicating asthma
• Asthma with Aspergillus sensitization
• 5.5-38.5%
• ABPA in asthma
• 2.5-22.3%
• Pooled prevalence 8.4%

9. Pathogenesis

10. Spore/conidia 2.5-3.5 mm
• Growth
• Secretes proteolytic enzymes
• Cellular dysfunction e.g. cilial disruption
• Invade epithelial cell
• Tissue disruption

11. Predisposing Factors
• Breakdown of local nonspecific immunity
• Mucociliary clearance mechanisms
• Preexisting lung disease
• Bronchiectasis in CF
• Viscous mucus layer  impared spore removal

12. Genetic Risk Factors
• HLA-DR2
• HLA-DR5
• Protective
• HLA-DQ2
• CF transmembrane conductance regulator gene mutation
•  Increased chances of Aspergillus colonization
• Surfactant protein-A2 polymorphisms
• Elevated levels of mannan-binding lectin due to the 1011A allele
• Toll-like receptor polymorphism

13. T-helper responses to A. fumigatus

14. Dewi IMW, Veerdonk FL, Gresnigt MS. The Multifaceted Role of T-Helper Responses in Host Defense against Aspergillus fumigatus. J Fungi 2017

16. Immune pathway in ABPA

17. Clinical Manifestation

18. Asymptomatic Mild asthma Respiratory failure

19. Symptoms
• Fever
• Malaise
• Weight loss
• Fatigue

20. Symptoms
• Respiratory symptoms
• Cough
• Expectoration
• Breathlessness
• Wheezing
• Hemoptysis
• Nasal symptoms
• Expectoration of golden brownish sputum plugs

21. Physical Examination
• Rhonchi
• Crepitation
• Bronchial sound
• Cyanosis
• Digital clubbing
• Cor pulmonale
• Hypertrophic osteoarthropathy

22. Imaging
• Transient pulmonary infiltrates
• Acute and exacerbation stage
• Due to mucoid impaction in bronchi
• Upper lobe predominant

23. Shah A, Panjabi C. Allergic bronchopulmonary aspergillosis: a perplexing clinical entity. Allergy Asthma Immunol Res. 2016 July;8(4):282-97

24. Shah A, Panjabi C. Allergic bronchopulmonary aspergillosis: a perplexing clinical entity. Allergy Asthma Immunol Res. 2016 July;8(4):282-97

25. Laboratory Findings
• Eosinophil count
• Skin testing with Aspergillus antigen
• Total serum IgE
• Specific IgE/IgG to A. fumigatus
• Precipitating antibody against A. fumigatus

26. Eosinophil Count
• Peripheral blood eosinophilia
• Sputum eosinophilia
• Absolute eosinophil count 1,000-3000/mL
• Found in other lung disease
• Maybe normal in corticosteroid treated

27. Skin Testing with Aspergillus Antigen
• Both type I and type III skin sensitivity
• Prick test then intradermal testing
• Not very specific
• Asthma 40%
• CF 56%

28. Nikolaizik WH, Weichel M, Blaser K, Crameri R. Intracutaneous tests with recombinant allergens in cystic fibrosis patients with allergic bronchopulmonary aspergillosis
and Aspergillus allergy. Am J Respir Crit Care Med 2002;165;916-21
50 CF patients (12 ABPA, 17 Aspergillus sensitization, 21 not sensitized)
Recombinant Af allergens (rAsp f 1, rAsp f 3, rAsp f 4 and rAsp f 6)

29. Total Serum IgE
• Rosenberg-Patterson >1,000 IU/mL ~2500 ng/mL
• Greenberger >417 IU/mL 1,000 ng/mL
• ISHAM Working Group >1,000 IU/mL

30. Specific IgE/IgG to A. fumigatus
• Positive
• Higher than control
• Very high level
• >0.35 kUA/L (ISHAM Working Group)
• High level of specific IgE to recombinant can detect ABPA in CF

31. Precipitating Antibodies Against A. fumigatus
Page ID, Richardson M, Denning DW. Antibody testing in aspergillosis-quo vadis?. Med Mycol 2015;53;417-39
Also found in
• Asthmatics without ABPA
• Aspergilloma
• Chronic pulmonary aspergillosis
High titer correlated with fibrosis and cavitation

32. Diagnosis

34. Staging

35. Greenberger PA, Patterson R. Allergic bronchopulmonary aspergillosis: model of bronchopulmonary disease with defined serologic, radiologic, pathologic
and clinical findings from asthma to fatal destructive lung disease. Chest 1987;91:165S-71S

36. Agarwal R, Chakrabarti A, Shah A, Gupta D, Meis JF, Guleria R, et al. Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and
classification criteria. Clin Exp Allergy 2013;43:850-73

37. Categories Features Severity
ABPA-S Serologic; all criteria except central bronchiectasis Mild
Mild-moderate airflow obstruction
ABPA-CB With central bronchiectasis Moderate
Moderate-severe airflow obstruction
ABPA-CB-
ORF
With central bronchiectasis plus other radiologic features, such as
pulmonary fibrosis, bleb, bullae, pneumothorax, parenchymal scarring,
emphysematous change, multiple cysts, fibrocavitary lesions, aspergilloma,
ground-glass appearance, collapse, mediastinal lymph node, pleural effusion
and thickening
Severe
Severe airflow obstruction
Radiologic Staging

38. Treatment

39. Goal of Treatment: AAAAI Committee Report
• Control symptoms of asthma or CF
• Prevent or treat pulmonary exacerbations of ABPA
• Reduce or remit pulmonary inflammation
• Mitigate progression to end-stage fibrotic or cavitary disease
Greenberger PA. Push RK, Demian JG, Luong A, Slavin RG, Knutsen AP. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunolol Pract 2014;2:703-8

40. Treatment
• Corticosteroids
• Antifungal agents
• Omalizumab

41. Stage I and III
• Regimen I†
• 0.5 MKD OD 2 weeks
• 0.5 MKD EOD 6-8 weeks
• Taper 2.5-5 mg q 2 weeks
• Regimen II‡
• 0.75 MKD 6 weeks
• 0.5 MKD 6 weeks
• Taper 5 mg q 6 weeks
• Duration 6-12 months as determined by disease activity
†Patterson R, Greenberger PA, Halwig JM: Allergic bronchopulmonary aspergillosis: natural history and classification of early disease by serologic and
roentgenographic studies. Arch Intern Med 1986;146:916-8
‡Agarwal R, Gupta D, Aggarwal AN, Behera D, Jindal SK: Allergic bronchopulmonary aspergillosis: lessons from 126 patients attending a chest clinic in north
India. Chest.130:442-8
‡Vlahakis NE, Aksamit TR: Diagnosis and treatment of allergic bronchopulmonary aspergillosis. Mayo Clin Proc 2001;76:930-8 2001

42. Corticosteroids
• Stage IV (steroid-dependent asthma)
• Usually required 10-40 mg for many years
• Stage V
• Daily prednisolone
• Intervention for cor pulmonale

43. Antifungal Agents
• Reduce fungal load
• Help control antigenic stimulus
• Decrease inflammatory response
• ╳natamycin, hamycin, amphotericin B, miconazole, clotrimazole,
ketoconakole
• Itraconazole
• 200 mg bid x4-6 months
• Taper over next 4-6 months
• Inhibit steroid metabolism

44. Antifungal Agents
• Itraconazole
• 200 mg bid x4-6 months
• Taper over next 4-6 months
• Inhibit steroid metabolism
• Voriconazole and posaconazole improve asthma severity 70%, 78%
• Itraconazole as first line?

46. Omalizumab
• Cystic fibrosis and asthma
• ↓Hospitalization
• ↓Exacerbation
• ↓Oral corticosteroids
• Use
• Corticosteroid-sparing agent
• Lift-threatening respiratory failure