Transcript No Slide Title

Chronic pulmonary aspergillosis
David W. Denning
Wythenshawe Hospital
University of Manchester
CLASSIFICATION OF ASPERGILLOSIS
Airways/nasal
exposure to
airborne
Aspergillus
Persistence
without disease
- colonisation of
the airways or
nose/sinuses
Invasive aspergillosis
• Acute (<1 month course)
• Subacute/chronic necrotising (1-3 months)
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)
CLASSIFICATION OF ASPERGILLOSIS
Airways/nasal
exposure to
airborne
Aspergillus
Persistence
without disease
- colonisation of
the airways or
nose/sinuses
Invasive aspergillosis
• Acute (<1 month course)
• Subacute/chronic necrotising (1-3 months)
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
• Allergic Aspergillus sinusitis (eosinophilic
fungal rhinosinusitis)
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)
50
45
40
35
30
25
20
15
10
5
0
G/G
G/A
A/A
CCPA
OTHER
ALL
CONTROLS
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 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; 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
Itra
Vori
Posa
02/04 06/04
>8
>8 Gly138Cys mutation
8
8
4
4
Howard et al, Int J Antimicrob Ag. 2006 In press
Long term voriconazole
Photosensitivity
an issue – use
sun block
Denning & Griffiths J Exp Dermatol 2001;26:648
www.aspergillus.org.uk