Chronic pulmonary aspergillosis

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Chronic pulmonary aspergillosis

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

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CLASSIFICATION OF ASPERGILLOSIS
Airways/nasal exposure to airborne Aspergillus

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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)

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Simple (single) aspergilloma
Patient RT December 2002 Cough (mild) tired
Wythenshawe Hospital
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Aspergilloma
Severo on www.aspergillus.org.uk
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Aspergillus precipitins
Severo on www.aspergillus.org.uk
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Chronic Cavitary Pulmonary Aspergillosis Normal
30 year female smoker
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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Multicavity disease is the hallmark of chronic
cavitary pulmonary aspergillosis (CCPA)
Wythenshawe Hospital
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Chronic cavitary pulmonary aspergillosis
Patient JP June 1999
Denning DW et al, Clin Infect Dis 2003 37(Suppl
3)S265-80
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Chronic Cavitary Pulmonary Aspergillosis, with
aspergilloma
Patient JP July 2001, untreated
Denning DW et al, Clin Infect Dis 2003 37(Suppl
3)S265-80.
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Chronic Fibrosing Pulmonary Aspergillosis
Patient JP April 2002, Untreated
Denning DW et al, Clin Infect Dis 2003 37(Suppl
3)S265-80.
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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
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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
• May have elevated total IgE and Aspergillus
  specific IgE (RAST)

Denning DW et al, Clin Infect Dis 2003 37S265
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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
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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
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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
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Role of surfactant
Wright JR Nat Rev Immunol 2005558.
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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
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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
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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
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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
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Treatment of chronic cavitary pulmonary
aspergillosis
Denning DW et al, Clin Infect Dis 2003 37S265
Jain Denning. J Infect 200652e133-7.
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CPA treatment IFN gamma?
Denning DW et al, Clin Infect Dis 2003 37(Suppl
3)S265-80.
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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.
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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
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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.org.uk
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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
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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
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Photosensitivity an issue use sun block
Long term voriconazole
Denning Griffiths J Exp Dermatol 200126648
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www.aspergillus.org.uk