Chronic pulmonary aspergillosis

David W. DenningWythenshawe Hospital

University of Manchester

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

Sub-acute invasive aspergillosis in AIDSSub-acute invasive aspergillosis in AIDS

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2 month history of cough and weight

loss

Sub-acute invasive aspergillosis in AIDSSub-acute invasive aspergillosis in AIDS

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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

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TimeframesTimeframes

IPA days/1-4 weeks

Subacute IPA/CNPA weeks/2-3 months

CCPA months/years

Aspergilloma months/years

AspergillomaAspergilloma

Patient RTDecember 2002

Cough (mild) &tired

Wythenshawe Hospital

Aspergilloma – may be mobile in the Aspergilloma – may be mobile in the cavitycavity

Upright Prone

Severo on www.aspergillus.man.ac.uk

AspergillomaAspergilloma

Severo on www.aspergillus.man.ac.uk

Histology of an aspergillomaHistology of an aspergilloma

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Aspergilloma due to Aspergilloma due to A. nigerA. niger and oxalosis and oxalosis

Oxalate crystals in wall of the aspergilloma

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Renal oxalosis

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

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Orderly hyphal growth on the inside of the cavity

Bilateral fibrocystic sarcoidosisBilateral fibrocystic sarcoidosis

Wythenshawe Hospital

Pt AR, Feb 2003

Bilateral fibrocystic sarcoidosisBilateral fibrocystic sarcoidosis

Wythenshawe Hospital

Pt AR, Feb 2004

Pre-existing cavities

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

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

Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis

Patient JAJan 2001

Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis

Patient JAFeb 2002

Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis

Patient JAApril 2003

Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary AspergillosisAspergillosis

Patient JAJuly 2003

Chronic Cavitary Pulmonary Chronic Cavitary Pulmonary Aspergillosis complicating ABPAAspergillosis complicating ABPA

Patient KMMay 2004

Wythenshawe Hospital

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

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

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

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

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%)

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

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

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.

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

Chronic cavitary pulmonary aspergillosis Chronic cavitary pulmonary aspergillosis an example of radiographic failurean example of radiographic failure

Patient SSApril 2004

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Patient SSJuly 2004, despite receiving itraconazole for 3 months

Chronic cavitary pulmonary aspergillosisChronic cavitary pulmonary aspergillosis

Patient RWSeptember 1992

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Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis

Patient RWJuly 1993

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Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis

Patient RWJune 2002

Stable, asymptomatic, normal inflammatory markers, just detectable Aspergillus precipitins

Itraconazole stopped after 5 years

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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

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Patient RWSeptember 1992

Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis

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Patient RWJune 2003

Conceptual frameworkConceptual framework

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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

Chronic fibrosing pulmonary Chronic fibrosing pulmonary aspergillosisaspergillosis

Patient RS March 2004

Denning DW et al, Clin Infect Dis 2003; 37:S265

Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis

Patient JP June 1999

Denning DW et al, Clin Infect Dis 2003; 37:S265

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

Chronic Fibrosing Pulmonary Chronic Fibrosing Pulmonary AspergillosisAspergillosis

Patient JPApril 2002

Denning DW et al, Clin Infect Dis 2003; 37:S265

Pathogenesis of cavity formationPathogenesis of cavity formation

Pathogenesis of unilateral fibrosisPathogenesis of unilateral fibrosis

?