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

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Presentation on theme: "Clinical and radiological presentation and diagnosis David W. Denning National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital]"— Presentation transcript:

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 Airways/nasal exposure to airborne Aspergillus Invasive aspergillosis Acute (<1 month course) Subacute/chronic necrotising (1-3 months) 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 Interaction of Aspergillus with the host A unique microbial-host interaction Immune dysfunction Frequency of aspergillosis Immune hyperactivity Frequency of aspergillosis Acute IA Subacute IA Aspergilloma Chronic pulmonary ABPA Severe asthma with fungal sensitisation Allergic sinusitis. After Casadevall & Pirofski, Infect Immun 1999;67:3703

5 Size of Aspergillus disease problem globally 1.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). 2.Chronic pulmonary aspergillosis after TB – 1.1M cases prevalence 3.Chronic pulmonary aspergillosis total - ~3M 4.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 1.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). 2.Chronic pulmonary aspergillosis after TB – 1.1M cases prevalence 3.Chronic pulmonary aspergillosis total - ~3M 4.Asthma 197M in adults, of which ~10-20% severe, UK and USA have very high prevalence rates 5.Allergic bronchopulmonary aspergillosis in asthma - ~4M worldwide (2.1% of adults referred with asthma) 6.Severe asthma with fungal sensitisation - ~6M worldwide (33% of 10% (severe only))

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

9 Chronic Pulmonary Aspergillosis

10 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 Camuset et al, Chest 2007:131:1435 9 patients with chronic cavitary pulmonary aspergillosis 15 with chronic necrotising pulmonary aspergillosis

12 Underlying diseases - CPA Smith, ISHAM 2009 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

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 Anonymous. Tubercle 1970;51:227 ~10% of all cases of pulmonary TB get CPA

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

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

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 Oxalate crystals in wall of the aspergilloma Severo on www.aspergillus.man.ac.uk Renal oxalosis

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

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 Severo on www.aspergillus.org.uk Patient 1 blood Patient 2 blood Patient 3 blood Patient 4 blood Patient 5 blood Patient 6 blood Aspergillus extract

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

29 Chronic cavitary pulmonary aspergillosis – CT reconstruction Wythenshawe Hospital

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

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 Baxter, Thorax 2011 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

37 CLASSIFICATION OF ASPERGILLOSIS Persistence without disease - colonisation of the airways or nose/sinuses Airways/nasal exposure to airborne Aspergillus Invasive aspergillosis Acute (<1 month course) Subacute/chronic necrotising (1-3 months) 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 Patient SY, Aspergillus Website Inhaled steroids

41 Proposed new criteria for ABPA 1.Serum IgE >1000 IU/mL 2.Asthma OR CF 3.Airway obstruction (ie CT scan/bronchoscopy) by or production of mucus plugs containing hyphae Which fungus? 1.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 ABPA Patient AL www.aspergillus.org.uk May 2010 January 2011 June 2011

45 Exacerbation of ABPA Patient AL www.aspergillus.org.uk September 2011

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

51 Severe Asthma and Fungal Sensitisation www.emphysema-copd.co.uk

52 Fungal exposure in asthmatics is related to: Life-threatening asthmatic attacks (ie thunderstorm asthma) Severe asthma and hospital admission Increased wheezing and symptoms Loss of medication control Allergic bronchopulmonary mycosis Eosinophilic fungal rhinosinusitis O'Hollaren, N Engl J Med 1991; 324: 359; and many others

53 Green et al, J Allergy Clin Immunol 2005;115:1043 Airborne fungal fragments Fungal fragment Diffusing allergen leeching out of fungus in contact with liquid

54 Bowyer et al, BMC Genomics 2006;7:251 Genomic analysis of allergens

55 Severe asthma and mould senstivity – Alternaria and Cladosporium Mild asthma – 564 (50%) Moderate asthma – 333 (29%) Severe asthma – 235 (21%) Zureik et al, Br Med J 2002;325:411

56 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 Mean sensitization score (mm) (Mean and 95% CI) Non-Mould allergens No Hospital Admission Single Admission Multiple Admissions ODriscoll et al, BMC Pulmonary Medicine 2005;5:4 Mould allergens No Hospital Admission Single Admission Multiple Admissions P= <0.0001

57 Colonisation in normal lungs Lass-Florl et al, Br J Haematol 1999;104:745 22 of 30 (73%) grew a fungus in both lung samples taken 10/30 (33%) grew >1 species

58 Asthma and Aspergillus Fairs et al, Am J Respir Crit Care Med 2010; July 16 79 adult asthmatics and 14 controls Patients sensitised to A. fumigatus compared with non- sensitised asthmatics had: lower lung function (% pred. FEV1 68% vs 88% p < 0.05), more bronchiectasis (68% versus 35% p < 0.05) and more sputum neutrophils (80.9% vs 49.5% p < 0.01).

59 Severe asthma and aspergillosis in ICU 57 of 357 (16%) admitted ICU with acute asthma Compared with 755 outpatients with asthma Aspergillus skin prick test used to screen for aspergillus hypersensitivity, if positive IgE etc for ABPA checked Aspergillus positiveABPA Asthma in ICU29/57 (51%) 22/57 (39%) Outpatient asthma90/755 (39%) 155/755 (21%) P value0.010.001 Agarwal et al, Mycoses 2009 Jan 24th

60 Severe asthma with invasive aspergillosis Felton et al Chest 2010;137:724

61 Severe asthma with fungal sensitisation (SAFS) Denning et al, Eur Resp J 2006; 27;27:615 Criteria for diagnosis Severe asthma (BTS step 4 or 5) AND RAST (IgE) positive for any fungus OR Skin prick test positive for any fungus AND Exclude ABPA (ie total IgE <1,000 iu/mL)

62 Comparison of ABPA and SAFS serology ABPA results normal range date 1 date 2 SAFS results Patient 1 2

63 ODriscoll, unpublished Skin prick testing – example of SAFS result Cladosporium +ve

64 Fungal sensitisation in severe asthma – skin prick test or RAST for diagnosis? N= 121 patients screened ODriscoll et al, Clin Exp Allergy. In press SPT + RAST both positive 100% 50% 43 10 13 34 SPT positive RAST negative SPT negative RAST positive SPT negative RAST negative } >23% discordant results

65 Fungal sensitisation in severe asthma – number sensitised to one or more fungi ODriscoll et al, Clin Exp Allergy. In press 1 2 3 4 5 6 7 N = 40 N = 20 29 11 12 3 7 7 Sensitisation to one or more fungi 13 sensitised to only Aspergillus 8 to Candida 3 to Trichophyton 3 to Penicillium 1 to Alternaria 1 to Cladosporium

66 Distinguishing different forms of aspergillosis Disease group CCPAABPA + CCPAABPASAFS n116169852 Median serum IgE level (IQR) 99.8 (26.4-350) (n=107) 2739 (1100-7500) (n=16) 2300 (1100-4550) (n=97) 370 (140-750) (n=52) Aspergillus specific IgG 93.6% (103/110)81.3% (13/16)65.4% (53/81)35.9% (14/39) Positive fungal culture 25% (29/116)25.0% (4/16)23.5% (23/98)21.2% (11/52) Positive specific IgE Positive SPT Mixed mouldN/T 88.9% (8/9)90.9% (20/30)100% (2/2) A. fumigatus37.7% (40/106)93.8% (15/16)96.9% (94/97)78.8% (41/52)90.9% (20/30) Alternaria alternata 10.0% (1/10)100% (10/10)77.5% (55/71)32.5% (13/40)47.4% (9/19) C. albicans33.3% (3/9)90.0% (9/10)81.4% (57/70)37.5% (15/25)52.6% (10/19) Cladosporium herbarum 20.0% (2/10)80.0% (8/10)70.4% (50/71)24.4% (10/41)35.5% (6/17) Penicillium chrysogenum 27.3% (3/11)100% (10/10)85.3% (58/68)30.0% (12/40)43.8% (7/16) Trichophyton mentagrophyte 33.3% (2/6)100% (3/3)65.2% (30/46)25.0% (9/36)23.1% (3/13)

67 Disease group CCPAABPA + CCPAABPASAFS n116169852 Median serum IgE level (IQR) 99.8 (26.4-350) (n=107) 2739 (1100-7500) (n=16) 2300 (1100-4550) (n=97) 370 (140-750) (n=52) Aspergillus specific IgG 93.6% (103/110)81.3% (13/16)65.4% (53/81)35.9% (14/39) Positive fungal culture 25% (29/116)25.0% (4/16)23.5% (23/98)21.2% (11/52) Positive specific IgE Positive SPT Mixed mouldN/T 88.9% (8/9)90.9% (20/30)100% (2/2) A. fumigatus37.7% (40/106)93.8% (15/16)96.9% (94/97)78.8% (41/52)90.9% (20/30) Alternaria alternata 10.0% (1/10)100% (10/10)77.5% (55/71)32.5% (13/40)47.4% (9/19) C. albicans33.3% (3/9)90.0% (9/10)81.4% (57/70)37.5% (15/25)52.6% (10/19) Cladosporium herbarum 20.0% (2/10)80.0% (8/10)70.4% (50/71)24.4% (10/41)35.5% (6/17) Penicillium chrysogenum 27.3% (3/11)100% (10/10)85.3% (58/68)30.0% (12/40)43.8% (7/16) Trichophyton mentagrophyte 33.3% (2/6)100% (3/3)65.2% (30/46)25.0% (9/36)23.1% (3/13) Distinguishing different forms of aspergillosis

68 Conceptual framework for CPA and IA Conceptual framework for CPA and IA www.aspergillus.org.uk Aspergilloma - CCPA - CNPA/subacute IPA - acute IPA Immune function Hyphal load in tissue Normal Massive Vascular invasion, necrosis, dissemination Granulomas, acute inflammation, central necrosis Chronic inflammation and fibrosis

69 Alternative Aspergillus diagnoses Aspergillus bronchitis Obstructing bronchial aspergillosis Invasive Aspergillus tracheobronchitis Community acquired Aspergillus pneumonia Sub-acute invasive pulmonary aspergillosis (often called chronic necrotising pulmonary aspergillosis or CNPA) Extrinsic allergic (bronchiol)alveolitis (EAA) Aspergillus empyema

70 Arendrup, Scand J Infect Dis 2006:38:945 6 th Jan 24 th Feb

71 Obstructing bronchial aspergillosis Patient ML Pre-bronchscopy Denning et al, New Engl J Med 1991;324: 654 Patient ML After bronchoscopy

72 Subacute invasive pulmonary aspergillosis in AIDS Patient HB Day +14, CD4 cells 84/uL Biopsy positive for Aspergillus Sambatakou, Eur J Clin Microbiol Infect Dis 2005;24:628

73 Conclusions CPA = 3 months of pulmonary cavitation or nodule +/- aspergilloma, with symptoms + Aspergillus IgG or precipitins positive CPA patients almost all have an underlying diagnosis ABPA = asthma (any severity) or cystic fibrosis + total IgE >1,000 + SPT or Aspergillus IgE positive. SAFS = severe asthma + fungal SPT or IgE positive + total IgE <1,000 Some patients have overlap syndromes and more than 1 Aspergillus diagnosis


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