chronic pulmonary aspergillosis david w. denning wythenshawe hospital university of manchester
TRANSCRIPT
![Page 1: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/1.jpg)
Chronic pulmonary aspergillosis
David W. DenningWythenshawe Hospital
University of Manchester
![Page 2: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/2.jpg)
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
![Page 3: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/3.jpg)
Sub-acute invasive aspergillosis in AIDSSub-acute invasive aspergillosis in AIDS
www.aspergillus.man.ac.uk
2 month history of cough and weight
loss
![Page 4: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/4.jpg)
Sub-acute invasive aspergillosis in AIDSSub-acute invasive aspergillosis in AIDS
www.aspergillus.man.ac.uk
![Page 5: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/5.jpg)
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
www.aspergillus.man.ac.uk
![Page 6: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/6.jpg)
TimeframesTimeframes
IPA days/1-4 weeks
Subacute IPA/CNPA weeks/2-3 months
CCPA months/years
Aspergilloma months/years
![Page 7: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/7.jpg)
AspergillomaAspergilloma
Patient RTDecember 2002
Cough (mild) &tired
Wythenshawe Hospital
![Page 8: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/8.jpg)
Aspergilloma – may be mobile in the Aspergilloma – may be mobile in the cavitycavity
Upright Prone
Severo on www.aspergillus.man.ac.uk
![Page 9: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/9.jpg)
AspergillomaAspergilloma
Severo on www.aspergillus.man.ac.uk
![Page 10: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/10.jpg)
Histology of an aspergillomaHistology of an aspergilloma
Severo on www.aspergillus.man.ac.uk
![Page 11: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/11.jpg)
Aspergilloma due to Aspergilloma due to A. nigerA. niger and oxalosis and oxalosis
Oxalate crystals in wall of the aspergilloma
Severo on www.aspergillus.man.ac.uk
Renal oxalosis
![Page 12: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/12.jpg)
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
Severo on www.aspergillus.man.ac.uk
Orderly hyphal growth on the inside of the cavity
![Page 13: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/13.jpg)
Bilateral fibrocystic sarcoidosisBilateral fibrocystic sarcoidosis
Wythenshawe Hospital
Pt AR, Feb 2003
![Page 14: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/14.jpg)
Bilateral fibrocystic sarcoidosisBilateral fibrocystic sarcoidosis
Wythenshawe Hospital
Pt AR, Feb 2004
Pre-existing cavities
![Page 15: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/15.jpg)
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
![Page 16: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/16.jpg)
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
![Page 17: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/17.jpg)
Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis
Patient JAJan 2001
![Page 18: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/18.jpg)
Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis
Patient JAFeb 2002
![Page 19: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/19.jpg)
Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis
Patient JAApril 2003
![Page 20: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/20.jpg)
Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis
Patient JAJuly 2003
![Page 21: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/21.jpg)
Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary Aspergillosis complicating ABPAAspergillosis complicating ABPA
Patient KMMay 2004
Wythenshawe Hospital
![Page 22: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/22.jpg)
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
![Page 23: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/23.jpg)
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
![Page 24: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/24.jpg)
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
![Page 25: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/25.jpg)
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
![Page 26: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/26.jpg)
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%)
![Page 27: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/27.jpg)
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
![Page 28: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/28.jpg)
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
![Page 29: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/29.jpg)
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.
![Page 30: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/30.jpg)
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
![Page 31: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/31.jpg)
Chronic cavitary pulmonary aspergillosis Chronic cavitary pulmonary aspergillosis an example of radiographic failurean example of radiographic failure
Patient SSApril 2004
www.aspergillus.man.ac.uk
Patient SSJuly 2004, despite receiving itraconazole for 3 months
![Page 32: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/32.jpg)
Chronic cavitary pulmonary aspergillosisChronic cavitary pulmonary aspergillosis
Patient RWSeptember 1992
www.aspergillus.man.ac.uk
![Page 33: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/33.jpg)
Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis
Patient RWJuly 1993
www.aspergillus.man.ac.uk
![Page 34: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/34.jpg)
Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis
Patient RWJune 2002
Stable, asymptomatic, normal inflammatory markers, just detectable Aspergillus precipitins
Itraconazole stopped after 5 years
www.aspergillus.man.ac.uk
![Page 35: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/35.jpg)
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
www.aspergillus.man.ac.uk
![Page 36: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/36.jpg)
Patient RWSeptember 1992
Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis
www.aspergillus.man.ac.uk
Patient RWJune 2003
![Page 37: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/37.jpg)
Conceptual frameworkConceptual framework
www.aspergillus.man.ac.uk
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
![Page 38: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/38.jpg)
Chronic fibrosing pulmonary Chronic fibrosing pulmonary aspergillosisaspergillosis
Patient RS March 2004
Denning DW et al, Clin Infect Dis 2003; 37:S265
![Page 39: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/39.jpg)
Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis
Patient JP June 1999
Denning DW et al, Clin Infect Dis 2003; 37:S265
![Page 40: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/40.jpg)
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
![Page 41: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/41.jpg)
Chronic Fibrosing Pulmonary Chronic Fibrosing Pulmonary AspergillosisAspergillosis
Patient JPApril 2002
Denning DW et al, Clin Infect Dis 2003; 37:S265
![Page 42: Chronic pulmonary aspergillosis David W. Denning Wythenshawe Hospital University of Manchester](https://reader036.vdocuments.us/reader036/viewer/2022062417/5515c36955034693758b474d/html5/thumbnails/42.jpg)
Pathogenesis of cavity formationPathogenesis of cavity formation
Pathogenesis of unilateral fibrosisPathogenesis of unilateral fibrosis
?