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Chronic pulmonary aspergillosis
David W. DenningWythenshawe Hospital
University of Manchester
Interaction of Interaction of AspergillusAspergillus with the host with the host
A unique microbial-host interactionA unique microbial-host interaction
Immune dysfunction
Frequency
of a
sperg
illosis
Immune hyperactivity
Frequency
of
asp
erg
illosi
s
Acute IA
Subacute IACNPA
AspergillomaChronic cavitaryChronic fibrosing
ABPAAllergic sinusitis
. www.aspergillus.man.ac.ukwww.aspergillus.man.ac.uk
Sub-acute invasive aspergillosis in AIDSSub-acute invasive aspergillosis in AIDS
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2 month history of cough and weight
loss
Sub-acute invasive aspergillosis in AIDSSub-acute invasive aspergillosis in AIDS
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Sub-acute invasive aspergillosisSub-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
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TimeframesTimeframes
IPA days/1-4 weeks
Subacute IPA/CNPA weeks/2-3 months
CCPA months/years
Aspergilloma months/years
AspergillomaAspergilloma
Patient RTDecember 2002
Cough (mild) &tired
Wythenshawe Hospital
Aspergilloma – may be mobile in the Aspergilloma – may be mobile in the cavitycavity
Upright Prone
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AspergillomaAspergilloma
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Histology of an aspergillomaHistology of an aspergilloma
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Aspergilloma due to Aspergilloma due to A. nigerA. niger and oxalosis and oxalosis
Oxalate crystals in wall of the aspergilloma
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Renal oxalosis
Early Aspergillus infection of a pulmonary Early Aspergillus infection of a pulmonary cavity – ‘pre-aspergilloma’cavity – ‘pre-aspergilloma’
Aspergillus growth on the surface of a pulmonary cavity
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Orderly hyphal growth on the inside of the cavity
Bilateral fibrocystic sarcoidosisBilateral fibrocystic sarcoidosis
Wythenshawe Hospital
Pt AR, Feb 2003
Bilateral fibrocystic sarcoidosisBilateral fibrocystic sarcoidosis
Wythenshawe Hospital
Pt AR, Feb 2004
Pre-existing cavities
Bilateral fibrocystic sarcoidosis, after 2 Bilateral fibrocystic sarcoidosis, after 2 months of corticosteroidsmonths of corticosteroids
Wythenshawe Hospital
Pt AR, April 2004
Pleural thickening
Small aspergilloma
New cavity formation
Bilateral fibrocystic sarcoidosis, 3 months Bilateral fibrocystic sarcoidosis, 3 months later, off steroids – now chronic cavitary later, off steroids – now chronic cavitary
aspergillosisaspergillosis
Wythenshawe Hospital
Pt AR, July 2004
Larger aspergilloma
New cavity formation
Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis
Patient JAJan 2001
Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis
Patient JAFeb 2002
Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis
Patient JAApril 2003
Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis
Patient JAJuly 2003
Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary Aspergillosis complicating ABPAAspergillosis complicating ABPA
Patient KMMay 2004
Wythenshawe Hospital
Chronic pulmonary aspergillosis – pre-Chronic pulmonary aspergillosis – pre-existing diseaseexisting 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 - Chronic pulmonary aspergillosis - presentationpresentation
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
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%)
Mannose Binding Lectin (MBL)- a key Mannose Binding Lectin (MBL)- a key part of the innate immune systempart of the innate immune system
Disulphide bondInteraction with
collectin receptor
Interaction withMASP
Exon 1
Exon 2
Exon 3
Exon 4
CRD
Ca binding site2+
Crosdale et al J Infect Dis 2001;184:653
Mannose Binding ProteinMannose 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
MutationsMutations
Eisen & Minchinton Clin Infect Dis 2003;37:1496
CPA and human gene defectsCPA and human gene defects
Probably not related to coeliac disease (<1 in 30)Unpublished
Innate immunity8 of 11pts had low MBL genotypes p=<0.05 (compared to normal controls)
Crosdale et al J Infect Dis 2001;184:653.
Treatment of chronic cavitary pulmonary aspergillosis
Denning DW et al, Clin Infect Dis 2003; 37:S265; Jain AAA 2004
Treatment No of courses Stable or improved (%)
Treatment failure /
progression
Toxicity
Itraconazole primary therapy
17 12 (71) 5 3
Voriconazole 17 9/11 (82) 2 12
Amphotericin B IV
11 9 (82) 2 7
Gamma IFN with itraconazole
3 3 0 3
Itraconazole maintenance after AmB IV
6 6 0 0
Chronic cavitary pulmonary aspergillosis Chronic cavitary pulmonary aspergillosis an example of radiographic failurean example of radiographic failure
Patient SSApril 2004
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Patient SSJuly 2004, despite receiving itraconazole for 3 months
Chronic cavitary pulmonary aspergillosisChronic cavitary pulmonary aspergillosis
Patient RWSeptember 1992
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Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis
Patient RWJuly 1993
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Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis
Patient RWJune 2002
Stable, asymptomatic, normal inflammatory markers, just detectable Aspergillus precipitins
Itraconazole stopped after 5 years
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Chronic cavitary pulmonary aspergillosis - relapseChronic cavitary pulmonary aspergillosis - relapse
Patient RWJanuary 2003
Marked change, with new cough, weight loss, increased inflammatory markers and Aspergillus precipitins
Itraconazole restarted
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Patient RWSeptember 1992
Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis
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Patient RWJune 2003
Conceptual frameworkConceptual framework
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Aspergilloma - CCPA - CNPA/subacute IPA - acute IPA
Imm
une
func
tion
Hyphal load in tissue
Normal
Massive
Vascular invasion, necrosis,
disseminationGranulomas, acute
inflammation, central necrosis
Chronic inflammation and fibrosis
Chronic fibrosing pulmonary Chronic fibrosing pulmonary aspergillosisaspergillosis
Patient RS March 2004
Denning DW et al, Clin Infect Dis 2003; 37:S265
Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis
Patient JP June 1999
Denning DW et al, Clin Infect Dis 2003; 37:S265
Chronic Cavitary Pulmonary Aspergillosis, Chronic Cavitary Pulmonary Aspergillosis, with aspergillomawith aspergilloma
Patient JP July 2001
Denning DW et al, Clin Infect Dis 2003; 37:S265
Chronic Fibrosing Pulmonary Chronic Fibrosing Pulmonary AspergillosisAspergillosis
Patient JPApril 2002
Denning DW et al, Clin Infect Dis 2003; 37:S265
Pathogenesis of cavity formationPathogenesis of cavity formation
Pathogenesis of unilateral fibrosisPathogenesis of unilateral fibrosis
?