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

Interaction of Aspergillus with the host A unique microbial-host interaction Acute IA ABPA Allergic sinusitis Subacute IA CNPA Frequency of aspergillosis Frequency of aspergillosis Aspergilloma Chronic cavitary Chronic fibrosing Immune dysfunction Immune hyperactivity . www.aspergillus.man.ac.uk www.aspergillus.man.ac.uk

Sub-acute invasive aspergillosis in AIDS 2 month history of cough and weight loss www.aspergillus.man.ac.uk

Sub-acute invasive aspergillosis in AIDS www.aspergillus.man.ac.uk

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 www.aspergillus.man.ac.uk

Timeframes IPA days/1-4 weeks Subacute IPA/CNPA weeks/2-3 months CCPA months/years Aspergilloma months/years

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

Aspergilloma – may be mobile in the cavity Upright Prone Severo on www.aspergillus.man.ac.uk

Aspergilloma Severo on www.aspergillus.man.ac.uk

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

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

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

Bilateral fibrocystic sarcoidosis Pt AR, Feb 2003 Wythenshawe Hospital

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

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

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

Chronic Cavitary Pulmonary Aspergillosis Patient JA Jan 2001

Chronic Cavitary Pulmonary Aspergillosis Patient JA Feb 2002

Chronic Cavitary Pulmonary Aspergillosis Patient JA April 2003

Chronic Cavitary Pulmonary Aspergillosis Patient JA July 2003

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

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

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

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 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

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

Chronic pulmonary aspergillosis -microbiology 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%) Denning DW et al, Clin Infect Dis 2003; 37:S265

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

Mannose Binding Protein Mutations 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 Eisen & Minchinton Clin Infect Dis 2003;37:1496

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.

Treatment failure / progression Treatment of chronic cavitary pulmonary aspergillosis Treatment No of courses Stable or improved (%) Treatment failure / progression Toxicity Itraconazole primary therapy 17 12 (71) 5 3 Voriconazole 9/11 (82) 2 12 Amphotericin B IV 11 9 (82) 7 Gamma IFN with itraconazole Itraconazole maintenance after AmB IV 6 Denning DW et al, Clin Infect Dis 2003; 37:S265; Jain AAA 2004

Chronic cavitary pulmonary aspergillosis an example of radiographic failure Patient SS April 2004 Patient SS July 2004, despite receiving itraconazole for 3 months www.aspergillus.man.ac.uk

Chronic cavitary pulmonary aspergillosis Patient RW September 1992 www.aspergillus.man.ac.uk

Chronic cavitary pulmonary aspergillosis Patient RW July 1993 www.aspergillus.man.ac.uk

Chronic cavitary pulmonary aspergillosis Patient RW June 2002 Stable, asymptomatic, normal inflammatory markers, just detectable Aspergillus precipitins Itraconazole stopped after 5 years www.aspergillus.man.ac.uk

Chronic cavitary pulmonary aspergillosis - relapse Patient RW January 2003 Marked change, with new cough, weight loss, increased inflammatory markers and Aspergillus precipitins Itraconazole restarted www.aspergillus.man.ac.uk

Chronic cavitary pulmonary aspergillosis Patient RW September 1992 Patient RW June 2003 www.aspergillus.man.ac.uk

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

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

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

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

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

Pathogenesis of cavity formation Pathogenesis of unilateral fibrosis ?