Chronic pulmonary aspergillosis

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Chronic pulmonary aspergillosis

• David W. Denning
• Wythenshawe Hospital
• University of Manchester

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Interaction of Aspergillus with the hostA unique
microbial-host interaction
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
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Sub-acute invasive aspergillosis in AIDS
2 month history of cough and weight loss
www.aspergillus.man.ac.uk
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Sub-acute invasive aspergillosis in AIDS
www.aspergillus.man.ac.uk
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Sub-acute invasive aspergillosis

• Less immunocompromised patients
• Slower progression of disease (gt 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
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Timeframes

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

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Aspergilloma
Patient RT December 2002 Cough (mild) tired
Wythenshawe Hospital
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Aspergilloma may be mobile in the cavity
Upright
Prone
Severo on www.aspergillus.man.ac.uk
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Aspergilloma
Severo on www.aspergillus.man.ac.uk
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Histology of an aspergilloma
Severo on www.aspergillus.man.ac.uk
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Aspergilloma due to A. niger and oxalosis
Renal oxalosis
Oxalate crystals in wall of the aspergilloma
Severo on www.aspergillus.man.ac.uk
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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
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Bilateral fibrocystic sarcoidosis
Pt AR, Feb 2003
Wythenshawe Hospital
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Bilateral fibrocystic sarcoidosis
Pre-existing cavities
Pt AR, Feb 2004
Wythenshawe Hospital
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Bilateral fibrocystic sarcoidosis, after 2 months
of corticosteroids
New cavity formation
Pleural thickening
Small aspergilloma
Pt AR, April 2004
Wythenshawe Hospital
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Bilateral fibrocystic sarcoidosis, 3 months
later, off steroids now chronic cavitary
aspergillosis
New cavity formation
Larger aspergilloma
Pt AR, July 2004
Wythenshawe Hospital
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Chronic Cavitary Pulmonary Aspergillosis
Patient JA Jan 2001
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Chronic Cavitary Pulmonary Aspergillosis
Patient JA Feb 2002
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Chronic Cavitary Pulmonary Aspergillosis
Patient JA April 2003
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Chronic Cavitary Pulmonary Aspergillosis
Patient JA July 2003
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Chronic Cavitary Pulmonary Aspergillosis
complicating ABPA
Patient KM May 2004
Wythenshawe Hospital
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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 37S265
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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 37S265
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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 (gt20), 13
  gt200 and 7 gt400
• 9 of 14 (67) had Aspergillus specific IgE (RAST)

Denning DW et al, Clin Infect Dis 2003 37S265
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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 (n1)
• Percutaneous biopsy hyphae in 1/7 cases -
  chronic inflammatory changes and fibrosis

Denning DW et al, Clin Infect Dis 2003 37S265
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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 37S265
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Mannose Binding Lectin (MBL)- a key part of the
innate immune system
Crosdale et al J Infect Dis 2001184653
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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 2003371496
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CPA and human gene defects

• Probably not related to coeliac disease (lt1 in
  30)
• Unpublished
• Innate immunity
• 8 of 11pts had low MBL genotypes plt0.05
  (compared to normal controls)

Crosdale et al J Infect Dis 2001184653.
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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 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
Denning DW et al, Clin Infect Dis 2003 37S265
Jain AAA 2004
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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
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Chronic cavitary pulmonary aspergillosis
Patient RW September 1992
www.aspergillus.man.ac.uk
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Chronic cavitary pulmonary aspergillosis
Patient RW July 1993
www.aspergillus.man.ac.uk
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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
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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
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Chronic cavitary pulmonary aspergillosis
Patient RW June 2003
Patient RW September 1992
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Conceptual framework
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
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Chronic fibrosing pulmonary aspergillosis
Patient RS March 2004
Denning DW et al, Clin Infect Dis 2003 37S265
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Chronic cavitary pulmonary aspergillosis
Patient JP June 1999
Denning DW et al, Clin Infect Dis 2003 37S265
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Chronic Cavitary Pulmonary Aspergillosis, with
aspergilloma
Patient JP July 2001
Denning DW et al, Clin Infect Dis 2003 37S265
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Chronic Fibrosing Pulmonary Aspergillosis
Patient JP April 2002
Denning DW et al, Clin Infect Dis 2003 37S265
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Pathogenesis of cavity formationPathogenesis of
unilateral fibrosis

• ?