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Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester.

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Presentation on theme: "Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester."— Presentation transcript:

1 Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester

2 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 CNPA Aspergilloma Chronic cavitary Chronic fibrosing ABPA Allergic sinusitis.

3 Sub-acute invasive aspergillosis in AIDS 2 month history of cough and weight loss

4 Sub-acute invasive aspergillosis in AIDS

5 Sub-acute invasive aspergillosis Less immunocompromised patients Slower progression of disease (> 1 month) Cavitary or nodular pulmonary disease typical Vascular invasion less common Dissemination less common Antigen testing less useful Antibody testing may be helpful in diagnosis

6 Timeframes IPAdays/1-4 weeks Subacute IPA/CNPAweeks/2-3 months CCPAmonths/years Aspergillomamonths/years

7 Aspergilloma Patient RT December 2002 Cough (mild) & tired Wythenshawe Hospital

8 Aspergilloma – may be mobile in the cavity Upright Prone Severo on

9 Aspergilloma

10 Histology of an aspergilloma Severo on

11 Aspergilloma due to A. niger and oxalosis Oxalate crystals in wall of the aspergilloma Severo on Renal oxalosis

12 Early Aspergillus infection of a pulmonary cavity – pre-aspergilloma Aspergillus growth on the surface of a pulmonary cavity Severo on Orderly hyphal growth on the inside of the cavity

13 Bilateral fibrocystic sarcoidosis Wythenshawe Hospital Pt AR, Feb 2003

14 Bilateral fibrocystic sarcoidosis Wythenshawe Hospital Pt AR, Feb 2004 Pre-existing cavities

15 Bilateral fibrocystic sarcoidosis, after 2 months of corticosteroids Wythenshawe Hospital Pt AR, April 2004 Pleural thickening Small aspergilloma New cavity formation

16 Bilateral fibrocystic sarcoidosis, 3 months later, off steroids – now chronic cavitary aspergillosis Wythenshawe Hospital Pt AR, July 2004 Larger aspergilloma New cavity formation

17 Chronic Cavitary Pulmonary Aspergillosis Patient JA Jan 2001

18 Chronic Cavitary Pulmonary Aspergillosis Patient JA Feb 2002

19 Chronic Cavitary Pulmonary Aspergillosis Patient JA April 2003

20 Chronic Cavitary Pulmonary Aspergillosis Patient JA July 2003

21 Chronic Cavitary Pulmonary Aspergillosis complicating ABPA Patient KM May 2004 Wythenshawe Hospital

22 Chronic pulmonary aspergillosis – pre-existing disease All 18 patients had prior pulmonary disease 9 TB, 5 with atypical mycobacteria 13 smokers or ex-smokers All 18 non-immunocompromised 3 excess alcohol Denning DW et al, Clin Infect Dis 2003; 37:S265

23 Chronic pulmonary aspergillosis - presentation Weight loss 16 / 18 (89%) Cough 15 / 18 (83%) Shortness of breath 9 / 18 (50%) Haemoptysis 9 / 18 (50%) Fatigue / malaise 5 / 18 (28%) Chest pain 3 / 18 (17%) Sputum production ++ 3 / 18 (17%) Fever 2 / 18 (11%) Denning DW et al, Clin Infect Dis 2003; 37:S265

24 Chronic pulmonary aspergillosis - serology All 18 patients had positive Aspergillus precipitins ( ) All 18 patients had elevated inflammatory markers, CRP, PV and / or ESR 14 of 18 (78%) had elevated total IgE (>20), 13 >200 and 7 >400 9 of 14 (67%) had Aspergillus specific IgE (RAST) Denning DW et al, Clin Infect Dis 2003; 37:S265

25 Chronic pulmonary aspergillosis – invasive procedures Lung resection - histological confirmation in 4 patients, hyphae in cavities, not tissue Bronchoscopic biopsy - negative for hyphae in 8/9 - chronic inflammatory changes, fibrosis ± granuloma formation (n=1) Percutaneous biopsy – hyphae in 1/7 cases - chronic inflammatory changes and fibrosis Denning DW et al, Clin Infect Dis 2003; 37:S265

26 Chronic pulmonary aspergillosis - microbiology Denning DW et al, Clin Infect Dis 2003; 37:S265 Sputum culture was positive - 10 patients sporadically Sputum microscopy was positive - 1 patient BAL culture positive in 4 of 10 (40%) Lung biopsy positive 1 of 5 patients (20%) Pleural aspiration 3 of 3 (100%)

27 Mannose Binding Lectin (MBL)- a key part of the innate immune system Crosdale et al J Infect Dis 2001;184:653

28 Mannose Binding Protein 5 mutations described 2 in promoter region (less important) 3 in open reading frame (M52, M54, M57) Codon 54 mutation present in 16% of Caucasians homozygous in 2% Defects associated with bacterial infections in children and hepatitis B carriage Mutations Eisen & Minchinton Clin Infect Dis 2003;37:1496

29 CPA and human gene defects Probably not related to coeliac disease (<1 in 30) Unpublished Innate immunity 8 of 11pts had low MBL genotypes p=<0.05 (compared to normal controls) Crosdale et al J Infect Dis 2001;184:653.

30 Treatment of chronic cavitary pulmonary aspergillosis Denning DW et al, Clin Infect Dis 2003; 37:S265; Jain AAA 2004 TreatmentNo of coursesStable or improved (%) Treatment failure / progression Toxicity Itraconazole primary therapy 1712 (71)53 Voriconazole17 9/11 (82)212 Amphotericin B IV 119 (82)27 Gamma IFN with itraconazole 3303 Itraconazole maintenance after AmB IV 6600

31 Chronic cavitary pulmonary aspergillosis an example of radiographic failure Patient SS April Patient SS July 2004, despite receiving itraconazole for 3 months

32 Chronic cavitary pulmonary aspergillosis Patient RW September 1992

33 Chronic cavitary pulmonary aspergillosis Patient RW July 1993

34 Chronic cavitary pulmonary aspergillosis Patient RW June 2002 Stable, asymptomatic, normal inflammatory markers, just detectable Aspergillus precipitins Itraconazole stopped after 5 years

35 Chronic cavitary pulmonary aspergillosis - relapse Patient RW January 2003 Marked change, with new cough, weight loss, increased inflammatory markers and Aspergillus precipitins Itraconazole restarted

36 Patient RW September 1992 Chronic cavitary pulmonary aspergillosis Patient RW June 2003

37 Conceptual framework Conceptual framework 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

38 Chronic fibrosing pulmonary aspergillosis Patient RS March 2004 Denning DW et al, Clin Infect Dis 2003; 37:S265

39 Chronic cavitary pulmonary aspergillosis Patient JP June 1999 Denning DW et al, Clin Infect Dis 2003; 37:S265

40 Chronic Cavitary Pulmonary Aspergillosis, with aspergilloma Patient JP July 2001 Denning DW et al, Clin Infect Dis 2003; 37:S265

41 Chronic Fibrosing Pulmonary Aspergillosis Patient JP April 2002 Denning DW et al, Clin Infect Dis 2003; 37:S265

42 Pathogenesis of cavity formation Pathogenesis of unilateral fibrosis ?


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