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Chronic pulmonary aspergillosis

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Title: Chronic pulmonary aspergillosis


1
Chronic pulmonary aspergillosis
  • David W. Denning
  • Wythenshawe Hospital
  • University of Manchester

2
CLASSIFICATION OF ASPERGILLOSIS
Airways/nasal exposure to airborne Aspergillus

3
CLASSIFICATION OF ASPERGILLOSIS
  • Invasive aspergillosis
  • Acute (lt1 month course)
  • Subacute/chronic necrotising (1-3 months)

Airways/nasal exposure to airborne Aspergillus
  • Chronic aspergillosis (gt3 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)

4
Simple (single) aspergilloma
Patient RT December 2002 Cough (mild) tired
Wythenshawe Hospital
5
Aspergilloma
Severo on www.aspergillus.org.uk
6
Aspergillus precipitins
Severo on www.aspergillus.org.uk
7
Chronic Cavitary Pulmonary Aspergillosis Normal
30 year female smoker
Patient JA Jan 2001
8
Chronic Cavitary Pulmonary Aspergillosis
Patient JA Feb 2002
9
Chronic Cavitary Pulmonary Aspergillosis
Patient JA April 2003
10
Chronic Cavitary Pulmonary Aspergillosis
Patient JA July 2003
11
Multicavity disease is the hallmark of chronic
cavitary pulmonary aspergillosis (CCPA)
Wythenshawe Hospital
12
Chronic cavitary pulmonary aspergillosis
Patient JP June 1999
Denning DW et al, Clin Infect Dis 2003 37(Suppl
3)S265-80
13
Chronic Cavitary Pulmonary Aspergillosis, with
aspergilloma
Patient JP July 2001, untreated
Denning DW et al, Clin Infect Dis 2003 37(Suppl
3)S265-80.
14
Chronic Fibrosing Pulmonary Aspergillosis
Patient JP April 2002, Untreated
Denning DW et al, Clin Infect Dis 2003 37(Suppl
3)S265-80.
15
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 37S265
16
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 37S265
17
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 2003371496
18
CPA and MBL defects
  • Study 1
  • 8 of 11 (72) had low MBL genotypes plt0.05
  • (compared to normal controls)
  • Study 2
  • 8 of 17 (47) had low MBL genotypes p0.0002

Crosdale et al J Infect Dis 2001184653. Vaid et
al, unpublished
19
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 200642
279-87
20
Role of surfactant
Wright JR Nat Rev Immunol 2005558.
21
CPA and surfactant A2 defects
  • CCPA patients had 32 and 22 frequency of 2 SPA2
    mutations, compared with normals (18 and 11)
  • (p0.021 and p0.044)

Vaid et al, unpublished
22
CPA and cytokine gene defects
  • 3 groups of patients
  • CCPA (n24)
  • Other aspergillosis, mostly allergic (n15)
  • Other caucasian controls (n130-660)
  • Polymorphisms in IL-10, IL-15, aTNF, ?IFN and
    TGFß detected by PCR

Sambatakou et al, Int J Immunogenet 2006 In press
23
CPA and IL-10 (-1082)
  • IL-10 (-1082) G allele (low IL-10, reduced
    inflammation) OR0.38 p0.0006

Sambatakou et al, Int J Immunogenet 2006 In press
24
CPA and cytokine gene defects
  • 3 groups of patients
  • CCPA (n24)
  • Other aspergillosis, mostly allergic (n15)
  • Other caucasian controls (n130-660)
  • Polymorphisms in IL-10, IL-15, aTNF, ?IFN and
    TGFß detected by PCR
  • CCPA patients have genotypes consistent with low
    IL-10, low TGFß, low aTNF , high IL-15 and high
    ?IFN
  • a TH2-driven response and poor inflammatory
    control, esp if chronically infected

Sambatakou et al Int J Immunogenetic 2006 In press
25
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 Denning. J Infect 200652e133-7.
26
CPA treatment IFN gamma?
Denning DW et al, Clin Infect Dis 2003 37(Suppl
3)S265-80.
27
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 200652e133-7.
28
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
29
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
30
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
31
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 gt8 gt8 Gly138Cys
mutation Vori 8 8 Posa 4 4
Howard et al, Int J Antimicrob Ag. 2006 In press
32
Photosensitivity an issue use sun block
Long term voriconazole
Denning Griffiths J Exp Dermatol 200126648
33
www.aspergillus.org.uk
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