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

CLASSIFICATION OF ASPERGILLOSIS 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 (SAFS) Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis) Persistence without disease colonisation of the airways or nose/sinuses Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see next slide), with probably a component of the inoculum size contributing to invasive disease.

CLASSIFICATION OF ASPERGILLOSIS 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 Persistence without disease - colonisation of the airways or nose/sinuses Allergic Allergic bronchopulmonary (ABPA) Extrinsic allergic (broncho)alveolitis (EAA) Asthma with fungal sensitisation Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis) Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see next slide), with probably a component of the inoculum size contributing to invasive disease. However chronic disease if usually seen in patients with apparently normal immune systems.

Simple (single) aspergilloma Patient RT December 2002 Cough (mild) & tired Wythenshawe Hospital

Aspergilloma Severo on www.aspergillus.org.uk

Aspergillus precipitins Severo on www.aspergillus.org.uk

Chronic Cavitary Pulmonary Aspergillosis Normal 30 year female smoker 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

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

Chronic cavitary pulmonary aspergillosis Patient JP June 1999 Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80

Chronic Cavitary Pulmonary Aspergillosis, with aspergilloma Patient JP July 2001, untreated Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80.

Chronic Fibrosing Pulmonary Aspergillosis Patient JP April 2002, Untreated Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80.

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

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) Denning DW et al, Clin Infect Dis 2003; 37:S265

Mannose Binding Protein - Mutations MBP sticks avidly to A. fumigatus hyphae in vitro 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 MBL defects Study 1 8 of 11 (72%) had low MBL genotypes p=<0.05 (compared to normal controls) Study 2 8 of 17 (47%) had low MBL genotypes p=0.0002 Crosdale et al J Infect Dis 2001;184:653. Vaid et al, unpublished

Innate immunity proteins - surfactant 5 surfactant proteins in man, SPA1, SPA2, SPB, SPC and SPD – all ‘collectin’ family SPB - single ORF polymorphism (Thr131Ile) associated with ARDS Exogenous SPD protective against murine IA Sano H & Kuroki Y. Molecular Immunology 2006;42: 279-87

Role of surfactant Wright JR Nat Rev Immunol 2005;5:58.

CPA and surfactant A2 defects CCPA patients had 32% and 22% frequency of 2 SPA2 mutations, compared with normals (18% and 11%) (p=0.021 and p=0.044) Vaid et al, unpublished

CPA and cytokine gene defects 3 groups of patients: CCPA (n=24) Other aspergillosis, mostly allergic (n=15) Other caucasian controls (n=130-660) Polymorphisms in IL-10, IL-15, αTNF, γIFN and TGFβ detected by PCR Sambatakou et al, Int J Immunogenet 2006 In press

CPA and IL-10 (-1082) IL-10 (-1082) G allele (low IL-10, reduced inflammation) OR=0.38 p=0.0006 Sambatakou et al, Int J Immunogenet 2006 In press

CPA and cytokine gene defects 3 groups of patients: CCPA (n=24) Other aspergillosis, mostly allergic (n=15) Other caucasian controls (n=130-660) Polymorphisms in IL-10, IL-15, αTNF, γIFN and TGFβ detected by PCR CCPA patients have genotypes consistent with low IL-10, low TGFβ, low αTNF , high IL-15 and high γIFN = a TH2-driven response and poor inflammatory control, esp if chronically infected Sambatakou et al Int J Immunogenetic 2006 In press

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 & Denning. J Infect 2006;52:e133-7.

CPA treatment – IFN gamma? Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80.

CPA treatment - principles Important defects in innate immunity so long term (i.e. life-long) antifungal treatment, if possible May fail itraconazole initially, respond to IV amphotericin B, and be successfully maintained on itraconazole Itraconazole failures may respond to voriconazole Caspofungin not very effective (personal observation) Gamma IFN helpful in some cases Monitor for azole resistance Jain & Denning J Infect 2006;52:e133-7.

Chronic cavitary pulmonary aspergillosis an example of radiographic failure Patient SS April 2004 Patient SS July 2004, after receiving itraconazole for 3 months and no clinical improvement www.aspergillus.org.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.org.uk

Chronic cavitary pulmonary aspergillosis - relapse Patient RW January 2003 Marked change, with new cough, weight loss, ↑CRP/ESR and ↑Aspergillus precipitins Itraconazole restarted www.aspergillus.org.uk

Chronic fibrosing pulmonary aspergillosis, with bilateral aspergillomas and azole resistance Patient SM June 2004 After treatment with Itraconazole and Voriconazole MICs 02/04 06/04 Itra >8 >8 Gly138Cys mutation Vori 8 8 Posa 4 4 Howard et al, Int J Antimicrob Ag. 2006 In press

Photosensitivity an issue – use sun block Long term voriconazole Photosensitivity an issue – use sun block Denning & Griffiths J Exp Dermatol 2001;26:648

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