Clinical and radiological presentation and diagnosis

1. Clinical and radiological presentation and diagnosis David W. Denning National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital] University of Manchester

2. The National Aspergillosis Centre 225-250 new patients with aspergillosis referred annually

3. CLASSIFICATION OF ASPERGILLOSIS Persistence without disease - colonisation of the airways or nose/sinuses • Invasive aspergillosis • Acute (<1 month course) • Subacute/chronic necrotising (1-3 months) Airways/nasal exposure to airborne Aspergillus • Chronic aspergillosis (>3 months) • Chronic cavitary pulmonary • Aspergilloma of lung • Chronic fibrosing pulmonary • Chronic invasive sinusitis • Maxillary (sinus) aspergilloma • Allergic • Allergic bronchopulmonary (ABPA) • Extrinsic allergic (broncho)alveolitis (EAA) • Asthma with fungal sensitisation • Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

4. ABPA Severe asthma with fungal sensitisation Allergic sinusitis Acute IA Interaction of Aspergillus with the hostA unique microbial-host interaction Subacute IA Frequency of aspergillosis Frequency of aspergillosis Aspergilloma Chronic pulmonary Immune dysfunction Immune hyperactivity . After Casadevall & Pirofski, Infect Immun 1999;67:3703

5. Size of Aspergillus disease problem globally • Over 200,000 patients develop IA annually. Key groups include ~10% of acute leukaemia (30,000) and stem cell and other transplants (7,500) and 1.3% of COPD patients admitted to hospital (60,000 IA cases). • Chronic pulmonary aspergillosis after TB – 1.1M cases prevalence • Chronic pulmonary aspergillosis total - ~3M • Asthma 197M in adults, of which ~10-20% severe, UK and USA have very high prevalence rates

6. How common is ABPA in asthma? 10/1390 (0.72%) 9/255 (3.5%) 6/264 (2.3%) Donnelly, Irish J Med Sci 1991;160:288; Eaton, Chest 2000;118:66; Al-Mobeireek, Resp Med 2001;98:341

7. Size of Aspergillus disease problem globally • Over 200,000 patients develop IA annually. Key groups include ~10% of acute leukaemia (30,000) and stem cell and other transplants (7,500) and 1.3% of COPD patients admitted to hospital (60,000 IA cases). • Chronic pulmonary aspergillosis after TB – 1.1M cases prevalence • Chronic pulmonary aspergillosis total - ~3M • Asthma 197M in adults, of which ~10-20% severe, UK and USA have very high prevalence rates • Allergic bronchopulmonary aspergillosis in asthma - ~4M worldwide (2.1% of adults referred with asthma) • Severe asthma with fungal sensitisation - ~6M worldwide (33% of 10% (severe only))

8. Interaction of Aspergillus with the hostA unique microbial-host interaction ABPA Severe asthma with fungal sensitisation Allergic sinusitis Acute invasive aspergillosis Human genetic influence on disease expression Subacute invasive aspergillosis Frequency of aspergillosis Frequency of aspergillosis Aspergilloma Chronic pulmonary aspergillosis Immune dysfunction Immune hyperactivity . After Casadevall & Pirofski, Infect Immun 1999;67:3703

9. Chronic Pulmonary Aspergillosis

10. Common symptoms • Common symptoms • Cough, usually productive • Shortness of breath • Weight loss • Tiredness • Coughing up blood • Chest ache / discomfort • Occasionally • Fever • Severe chest pain from rib fracture • Additional chest infections • Angina and heart attacks (chronic inflammation)

11. Underlying diseases 9 patients with chronic cavitary pulmonary aspergillosis15 with chronic necrotising pulmonary aspergillosis Camuset et al, Chest 2007:131:1435

12. Underlying diseases - CPA • Classical tuberculosis * • Atypical tuberculosis * • Allergic bronchopulmonary aspergillosis * • Lung cancer survivor * • Pneumothorax * • COPD/emphysema * • Sarcoidosis (stage II/III) * • Rheumatoid arthritis • Thoracic surgery • Asthma • Chest radiotherapy • None * Common Smith, ISHAM 2009

13. Chronic pulmonary aspergillosis – pre-existing disease Prior pulmonary disease esp: Atypical mycobacteria pulmonary infection Sarcoidosis Tuberculosis Recurrent pneumothorax Prior pulmonary surgery ABPA Denning DW et al, Clin Infect Dis 2003; 37:S265

14. Frequency of chronic pulmonary aspergillosis after TB ~10% of all cases of pulmonary TB get CPA Anonymous. Tubercle 1970;51:227

15. Cavities Cavities Acute tuberculosis Before After treatment Cavities No cavities Lee, Eur J Radiol 2008; 67:100;

16. Chronic pulmonary aspergillosis Infection of the lung by Aspergillus Single fungal ball or aspergilloma in a pre-existing cavity

17. Simple (single) aspergilloma Patient RK Haempotysis, nil else Positive Aspergillus antibodies in blood Lobectomy Wythenshawe Hospital

18. Aspergillomas from 2 patients Wythenshawe Hospital; Severo on www.aspergillus.org.uk

19. Histology of an aspergilloma Severo on www.aspergillus.man.ac.uk

20. Aspergillus fumigatus

21. Aspergilloma due to A. niger and oxalosis Renal oxalosis Oxalate crystals in wall of the aspergilloma Severo on www.aspergillus.man.ac.uk

22. Early Aspergillus infection of a pulmonary cavity – ‘pre-aspergilloma’ Orderly hyphal growth on the inside of the cavity Aspergillus growth on the surface of a pulmonary cavity Severo on www.aspergillus.man.ac.uk

23. ‘Multicavity’ disease is the hallmark of chronic cavitary pulmonary aspergillosis (CCPA) Wythenshawe Hospital

24. Aspergilloma #3 – spatially ordered isolates from multiple cavities Bowyer et al, unpublished

25. Aspergillus precipitins (Aspergillus antibody (IgG) ) in blood Patient 2 blood Patient 3 blood Patient 1 blood Aspergillus extract Patient 4 blood Patient 6 blood Patient 5 blood Severo on www.aspergillus.org.uk

26. Aspergillus IgG serology Baxter, AAA 2010;Abstr 51

27. Chronic pulmonary aspergillosis - serology All 18 patients had positive Aspergillus precipitins (1+-4+) All 18 patients had elevated inflammatory markers, CRP, PV and / or ESR May have elevated total IgE and Aspergillus specific IgE (RAST) Only 40% have a positive sputum culture Denning DW et al, Clin Infect Dis 2003; 37:S265

28. Chronic pulmonary aspergillosis Infection of the lung by Aspergillus Single fungal ball or aspergilloma in a pre-existing cavity Chronic cavitary pulmonary aspergillosis +/- fungal ball

29. Chronic cavitary pulmonary aspergillosis – CT reconstruction Wythenshawe Hospital

30. Chronic cavitary pulmonary aspergillosis (CCPA) – sputum production Aspergillus cultures positive in CCPA in 10-40% of cases only Wythenshawe Hospital

31. ‘Multicavity’ disease is the hallmark of chronic cavitary pulmonary aspergillosis (CCPA) Wythenshawe Hospital

32. Chronic cavitary pulmonary aspergillosis (CCPA) – haemoptysis Wythenshawe Hospital

33. Chronic Cavitary Pulmonary Aspergillosis Normal 30 year female smoker Patient JA Jan 2001

34. Chronic Cavitary Pulmonary Aspergillosis Patient JA April 2003

35. Multifocal cavities with aspergillomas – unrecognised phenotype Wythenshawe Hospital

36. 18F-FDG PET positive pulmonary nodules in aspergillosis – a differential diagnosis of lung cancer 10 patients Presentations like lung cancer 1 subacute IPA 1 ABPA 1 aspergilloma 7 CPA Aspergillus IgG 28 ->200 mg/L All positive on histology Baxter, Thorax 2011

37. CLASSIFICATION OF ASPERGILLOSIS Persistence without disease - colonisation of the airways or nose/sinuses • Invasive aspergillosis • Acute (<1 month course) • Subacute/chronic necrotising (1-3 months) Airways/nasal exposure to airborne Aspergillus • Chronic aspergillosis (>3 months) • Chronic cavitary pulmonary • Aspergilloma of lung • Chronic fibrosing pulmonary • Chronic invasive sinusitis • Maxillary (sinus) aspergilloma • Allergic • Allergic bronchopulmonary (ABPA) • Extrinsic allergic (broncho)alveolitis (EAA) • Asthma with fungal sensitisation • Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

38. Allergic Bronchopulmonary Aspergillosis

39. ABPA – Diagnostic clues Asthma/CF not well controlled History of ‘pneumonia’ History of coughing up plugs, or paroxysms of coughing that clear when chest clears Central bronchiectasis on CT scan, or mucoid impaction Eosinophilia Rare cases in non-asthmatics, non-CF patients

40. Asthma – variable airflow obstruction Inhaled steroids Patient SY, Aspergillus Website

41. Proposed new criteria for ABPA Serum IgE >1000 IU/mL Asthma OR CF Airway obstruction (ie CT scan/bronchoscopy) by or production of mucus plugs containing hyphae Which fungus? Fungal sensitisation (IgE or SPT) and/or fungus detected in respiratory secretions Knutsen et al, AAAAI Task Force on Fungus and Asthma

42. ABPA - March – doing well FEV1 = 3.00 Aspergillus IgE = 31 IgE = 1900. No treatment

43. September – episode of pneumonia FEV1 = 1.6. IgE = 3000 Aspergillus IgE = 52.5. Exacerbation of ABPA

44. Exacerbation of ABPAPatient AL June 2011 January 2011 May 2010 www.aspergillus.org.uk

45. Exacerbation of ABPAPatient AL September 2011 www.aspergillus.org.uk

46. Mucoid impaction due to ABPA www.aspergillus.org.uk

47. Mucoid impaction due to ABPA www.aspergillus.org.uk

48. Sputum in ABPA www.aspergillus.org.uk

49. ABPA – bronchoscopy views showing mucous plugging www.aspergillus.org.uk

50. A. fumigatus in BAL and in bronchial tissue in ABPA