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Chronic Pulmonary Aspergillosis
Aspergillosi polmonare cronica
David W. Denning
Director, National Aspergillosis Centre
University Hospital South Manchester
[Wythenshawe Hospital]
The University of Manchester
Number of patients with aspergillosis in
EU
167,500 ABPA continuous
680,000 -1,700,000 SAFS cont.
Frequency of aspergillosis
Acute Invasive
Subacute Invasive
ABPA
Severe asthma with
fungal sensitisation
Allergic sinusitis
Aspergilloma
Chronic cavitary
Chronic fibrosing
Locally invasive
Frequency of aspergillosis
30,000 - 70,000 / year
>15,000 continuous
Immune dysfunction
Immune hyperactivity
.
After Casadevall
& Pirofski, Infect Immun 1999;67:3703
Chronic pulmonary aspergillosis
Infection of the lung by Aspergillus
Single fungal
ball or
aspergilloma
in a preexisting cavity
Simple (single) aspergilloma
Patient RK
Haempotysis,
nil else
Positive
Aspergillus
antibodies in
blood
Lobectomy
Wythenshawe Hospital
Aspergillus precipitins (Aspergillus
antibody (IgG) ) in blood
Patient 2
blood
Patient 3
blood
Patient 1
blood
Aspergillus
extract
Patient 4
blood
Patient 6
blood
Patient 5
blood
Severo on www.aspergillus.org.uk
Aspergillomas from 2 patients
Wythenshawe Hospital; Severo on www.aspergillus.org.uk
Aspergillus fumigatus
occasionally other species
Chronic pulmonary aspergillosis
Infection of the lung by Aspergillus
Single fungal
ball or
aspergilloma
in a preexisting cavity
Chronic
cavitary
pulmonary
aspergillosis
+/- fungal ball
Symptoms in CPA
Common symptoms
• Cough, usually productive
• Shortness of breath
• Weight loss
• Tiredness
• Coughing up blood
• Chest ache / discomfort
Occasionally
• Fever
• Severe chest pain from rib fracture
• Additional chest infections
• Angina and heart attacks (chronic inflammation)
Underlying diseases in patients with CPA (%)
Classical tuberculosis
Atypical tuberculosis
ABPA
COPD/emphysema
Pneumothorax
Lung cancer survivor
Pneumonia
Sarcoidosis (stage II/III)
Thoracic surgery
Rheumatoid arthritis
Asthma / SAFS
Ankylosing spondylitis
None
Smith
17
16
14
33
17
10
22
7
14
4
12
4
1
0thers
31-81
?
12
42-56
12-17
?
9-12
12-17
8-11
2
6-12
2-11
15
Smith, unpublished
‘Multicavity’ disease is the hallmark of chronic
cavitary pulmonary aspergillosis (CCPA)
Wythenshawe Hospital
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
Chronic cavitary pulmonary aspergillosis (CCPA) –
sputum production
Wythenshawe Hospital
Chronic cavitary pulmonary aspergillosis (CCPA) –
coughing up blood (haemoptysis)
Wythenshawe Hospital
Chronic pulmonary aspergillosis
Infection of the lung by Aspergillus
Single fungal
ball or
aspergilloma
in a preexisting cavity
Invasive
aspergillosis
/community
acquired
infection
Chronic
cavitary
pulmonary
aspergillosis
+/- fungal ball
Chronic
fibrosing
pulmonary
aspergillosis
+/- fungal ball
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.
CPA and immune defects
Mannose binding lectin
Surfactant A2
Toll-like Receptor 4
Gamma IFN production
Th2 dominated cytokine profile
Poor responses to other common bacteria
(Pneumococcus and Haemophilus)
Outcome untreated
Prognosis of chronic pulmonary aspergillosis
with an aspergilloma (1956-80)
Jewkes, Thorax 1983;38:572
Prognosis of chronic pulmonary aspergillosis
with an aspergilloma (1987)
Tomlinson & Sahn, Chest 1987;92:505
Antifungal therapy
IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327
CPA and coughing up blood
(haemoptysis)
• Minor haemoptysis common
• Manageable with tranexamic acid
orally
• Bronchial embolisation a good
option, if vessel can be embolised
& patient can lie flat for 2-3
hours
CPA and surgery
Survival from CPA
Korea
Nam, Int J Infect Dis 2009; epub
Stopping treatment after good
response ?
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
Resistance ?
Chronic cavitary pulmonary aspergillosis
(CCPA) in HIV February 2005
32 yr old from Malawi, on HAART Rx
- haemoptysis
- Aspergillus precipitin titre 16
CT scan shows 2 large cavities with aspergillomas,
with additional lesions (October 2005)
Surgical
removal would
require left
lung removal
So treated with
itraconazole
CCPA in HIV
February 2007
On HAART Rx, with low viral load, CD4 count >200
- New haemoptysis despite itraconazole
- Aspergillus precipitin titre to 32
MICs A. fumigatus Feb 2007
CXR & CT scan showed expansion of lower cavity
Itraconazole = >8.0mg/mL resistant
Voriconazole = 0.5 mg/mL sensitive
Posaconazole = 1.0 mg/mL resistant
February 2007
April 2007
Azole resistance in Manchester
70
Multi-azole resistant
11%
5%
Itraconazole & posaconazole resistant
60
Itraconazole resistant
Fully susceptible
s
Number of patient cases
17%
50
7%
5%
40
3%
0%
30
0%
5%
20
7%
0%
0%
1997
1998
10
0
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
Year
Howard et al, Emerg Infect Dis 2009;15:1068
CPA treatment - principles
• Important defects in innate immunity so long term (i.e.
life-long) antifungal treatment, if possible
• Itraconazole, voriconazole and posaconazole all
effective, but adverse events
• Short or long courses of amphotericin B useful for
patients with azole therapy failure
• Gamma IFN helpful in some cases
• Monitor for azole resistance
.
www.aspergillus.org.uk