Disease progression and approaches
to therapy
David W. Denning
Director, National Aspergillosis Centre
University Hospital South Manchester
[Wythenshawe Hospital]
The University of Manchester
Chronic Pulmonary Aspergillosis
RUL cavity - Patient RW
December 1991
Thought to have lung carcinoma as
smoker
RU lobectomy
2-cm cavity with necrotic contents
associated with local bronchiectasis and
thickening of the pleura.
Surrounding lung showed severe
emphysema with fibrosis. The cavity
was in an area of cystic bronchiectasis.
The cavity contained a fungus ball
without invasion or tissue eosinophilia.
One necrotizing granuloma seen. AFB
stains negative and cultures negative
for TB: Fungal cultures not done.
He was thought cured because the
whole lesion was resected.
Denning DW et al, Clin Infect Dis 2003; 37:S265
Chronic cavitary pulmonary
aspergillosis - RW
September 1992
3 months are presenting with haemoptysis
Aspergillus precipitins 3+
BAL – A. fumigatus
July 1993
Denning DW et al, Clin Infect Dis 2003; 37:S265
Chronic cavitary pulmonary
aspergillosis - RW
July 1993
Bilateral fibrocystic sarcoidosis
Pt AR, Feb 2003
Bilateral fibrocystic sarcoidosis
Pre-existing cavities
Pt AR, Feb 2004
Bilateral fibrocystic sarcoidosis, after 2
months of corticosteroids
New cavity
formation
Pleural thickening
Small aspergilloma
Pt AR, April 2004
Bilateral fibrocystic sarcoidosis, 3 months later,
off steroids – now chronic cavitary aspergillosis
New cavity
formation
Larger aspergilloma
Pt AR, July 2004
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 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
transforming to fibrosing aspergillosis
July 2001, untreated
Patient JP, June 1999
April 2003, untreated
Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80
Progression of CCPA or regression?
2005 on AmB
2007 on no Rx
2010 still on no Rx
Progression of CCPA or regression?
1992
1994 on no Rx
1997 still on no Rx
Progression of CCPA or regression?
Mar 2007
Dec 2005
Sept 2006
Development of chronic fibrosing
pulmonary aspergillosis on therapy
Chronic Cavitary Pulmonary Aspergillosis
complicating ABPA
Patient KM
May 2004
ABPA exacerbation – patient VE
August 2011
September 2011
ABPA exacerbation – patient AL
May 2010
May 2011
June 2011
After
prednisolone
ABPA CT after exacerbation – patient AL
May 2010
Prognosis
CPA + aspergilloma
UK (1956-80)
CPA + aspergilloma
USA (1987)
CPA + subacute IA
Korea (1995-2007)
Jewkes, Thorax 1983;38:572;
Tomlinson, Chest 1987;92:505;
Nam Int J Infect Dis 2010;14:e479;
CPA and surgery
• Single aspergillomas are amenable to surgery
• CCPA (complex aspergilloma) has a high complication
rate with surgery (mortality >5%, morbidity >30%)
• Haemoptysis, chronic ill-health and contraindications or
intolerance of azole antifungal therapy reasonable
indications
• Azole resistance also a new indication
Simple (single) aspergilloma
Patient RK
Haempotysis,
nil else
Positive
Aspergillus
antibodies in
blood
Lobectomy
Wythenshawe Hospital
Simple (single) aspergilloma
Patient NM
August 2006
May 2009
Community acquired
New cough
pneumonia requiring
ICU care
Positive Aspergillus
antibodies in blood
Lobectomy
Wythenshawe Hospital
Surgical results from removal of single
aspergilloma
8 of 8 simple aspergillomas resected successfully, no
deaths (France)
14 of 16 simple aspergillomas resected successfully,
bleeding and wound infection complications (1 each),
no deaths (Korea)
8 of 8 simple aspergillomas resected successfully, no
complications or deaths (India)
12 of 12 simple aspergillomas resected successfully, no
complications or death (Egypt)
Regnard, Ann thorac Surg 2000;69:898, Kim, Ann Thorac Surg 2003;79:294, Pratap Ind J
Chest Dis 2007; 49:23, Brik, Eur J Cardiothorac surg 2008;34:882
Treatment
Antifungal therapy
IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327
CPA and 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
Fluid level
Patient O’S
Pre-aspiration
Albumin 27
CRP 150
10mL thick pus aspirated under U/S
Leucocytes +++,
Bacterial culture negative
A. fumigatus grown
Wythenshawe Hospital
CPA treatment - principles
• Important defects in innate immunity so long term (i.e.
life-long) antifungal treatment, if possible
• Some patients appear not to progress, but should to be
kept under observation, as progression may be
subclinical
• Minimise other causes of lung infection with
immunisation and antibiotics
• Itraconazole, voriconazole and posaconazole all
effective, but adverse events
• Amphotericin B useful for oral azole therapy and
failure
• Gamma IFN helpful in some cases
• Monitor for azole resistance
Allergic Bronchopulmonary
Aspergillosis
and
Severe Asthma with Fungal
Sensitisation
Therapy of allergic aspergillosis
IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327
Therapy of allergic aspergillosis
Knutsen et al. J All Clin Immunol In press
Bronchiectasis complicating ABPA
Wythenshawe Hospital
ABPA and development of CPA
1985
1981
2002
1995
1993
www.aspergillus.org.uk
CPA complicating ABPA – Patient MT
2008
2011
Denning et al, unpublished
CPA complicating ABPA – Patient MT
2011 All new findings
CPA complicating
ABPA
3 patients with
longstanding asthma
and ABPA
Note the pleural
fibrosis with and
without local
cavitation
Denning et al, unpublished
Chest pain
VA presented with significant right sided lateral
chest pain. Underlying diagnosis of bronchiectasis
What should you do?
CT san sowing R sided
bronchiectasis
Isotope bone scan showing 2 rib
fractures laterally
Wythenshawe Hospital
ABPA/SAFS treatment - principles
• Variable natural history, so individualise therapy
• Short term goal is minimise symptoms and impact of
activities of life
• Long term goal is to prevent or minimise complications
of bronchiectasis and chronic pulmonary aspergillosis
and fibrosis
• Concurrent or additional bacterial and/or viral
infections common, especially if bronchiectasis present.
• Inhaled and/or oral corticosteroids important for
exacerbations, but should be minimised between
episodes
• Azithromycin and hypertonic saline often helpful
• Antifungal therapy response may be dramatic, but some
issues with therapy