LED BY GRAHAM ATHERTONSUPPORTED BY
NAC CENTRE MANAGER CHRIS HARRIS
CPA AND THE USE OF ITRACONAZOLEDAVID DENNING- DIRECTOR OF THE NATIONAL ASPERGILLOSIS
CENTRE
NATIONAL ASPERGILLOSIS CENTREUHSM
MANCHESTER
Support Meeting for Aspergillosis Patients &
Carers
Fungal Research Trust
Programme
1.30 David Denning – NAC Director 2.00 Graham Atherton – Your subject (IgE) 2.30 Patients Discussion (Break) 3.00 Group discussion/Requests for information
Genomics Research – the first major breakthroughs Manchester Fungal Infection Group (MFIG) Patients survey
3.20 Q & A from the floor or online
Treating chronic pulmonary aspergillosis – how do assess
response and what confuses us
David W. DenningNational Aspergillosis Centre, University Hospital of South
ManchesterThe University of Manchester
Different patterns of CPA
Radiological response varies by subtype of CPA
Chronic cavitary pulmonary aspergillosis
National Aspergillosis Centre
Chronic fibrosing pulmonary aspergillosis
Different patterns of CPA
Aspergillus nodule Simple aspergilloma
Simple (single) aspergilloma
Patient RK
Haempotysis, nil else
Positive Aspergillus antibodies in blood
Lobectomy and cured
Howard et al. Mycoses 2013;56:434
Aspergillus nodule
Patient BJ
Incidental discovery, thought to be carcinoma
Positive Aspergillus antibodies in blood
Biopsy showed Aspergillus
Treated with itraconazole
Farid et al, J Cardiothorac Surg 2013;8:180
Objectives of antifungal therapy
Very ill patients:Save their lives with (usually) IV and then oral therapy
Quite ill patients:Improve quality of life by minimising symptomsPrevent further haemoptysis (coughing blood)Stop progression of scarring in the lungPrevent the emergence of antifungal resistanceAvoid antifungal toxicity
Patients with few symptomsStop progression of scarring in the lungPrevent the emergence of antifungal resistanceAvoid antifungal toxicity
Randomised controlled open comparison of micafungin and voriconazole for chronic
pulmonary aspergillosis
Kohno et al. J Infect Dis 2010;61:410
Micafungin 150-300mg/d versus voriconazole 12 ➞ 8mg/Kg/d107 patients with CPA 2-4 weeks treatment
Felton, Clin Infect Dis 2010; 51:1383.
CPA and voriconazole Rx
Camuset et al, Chest 2007:131:1435
9 patients with chronic cavitary pulmonary aspergillosis15 with chronic necrotising pulmonary aspergillosis
13/24 (54%) primary therapy with voriconazole3 intolerant of voriconazoleMedian duration of Rx 6.4 mos (4-36)
Time to initial response with posaconazole therapy
6 months 12 months
Mean
95% confidence interval
Felton et al. Clin Infect Dis 2010; 51:1383
Oral itraconazole
35%
41%Stable
Improved Standard care No antifungal
23%
7%
29%
64%Deterioration
Impact of oral itraconazole therapy for chronic pulmonary aspergillosis after TB over 6 months
Agarwal R, et al, Mycoses. 2013 Mar 18. doi: 10.1111/myc.12075.
Chronic pulmonary aspergillosis – quality of life improvement to azole therapy using SGRQ over 12 months
Al-shair et al, Clin Infect Dis 2013, Online
All patients
n= 71 66 36
Posaconazole Voriconazole Itraconazole
n= 25 23 7 n= 24 24 15n= 19 16 12
ImprovedStableDeteriorated
Progression of CCPA
1992 1994 on no Rx 1997 still on no Rx
April 2003, untreated
July 2001, untreated
Chronic cavitary pulmonary aspergillosis transforming to fibrosing
aspergillosis
Patient JP, June 1999
Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80
Chronic cavitary pulmonary aspergillosis – CT reconstruction
Wythenshawe Hospital
Aspergillus IgG in blood
Falling levels is good, but takes months or years
Bilateral fibrocystic sarcoidosis – no symptoms
Pt AR, Feb 2004
Pre-existing cavities
Bilateral fibrocystic sarcoidosis, after 2 months of prednisolone
Pt AR, April 2004
Pleural thickening
Small aspergilloma
New cavity formation
Treated with prednisolone - 3 months later, off steroids – now chronic cavitary
aspergillosis
Pt AR, July 2004
Larger aspergilloma
New cavity formation
Chronic cavitary pulmonary aspergillosis - an example of radiographic failure
Patient SSApril 2004
www.aspergillus.org.uk
Patient SSJuly 2004, despite receiving itraconazole for 3 months
Chronic pulmonary aspergillosis - response to itraconazole after 6 months therapy, compared to
Oral itraconazole
6 mo 12 mo
35%
41%Stable
Improved
Standard care
6 mo 12 mo
23%
7%
29%
64% 71% 53%
7%
21%
24%
24%
Deterioration30% relapse off therapy in 6 months
Natural history with no therapy over 12 months
Agarwal R, et al, Mycoses. 2013 Mar 18. doi: 10.1111/myc.12075.
Chronic cavitary pulmonary aspergillosis
Patient RWJune 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 RWJanuary 2003
Marked change, with new cough, weight loss, ↑CRP/ESR and ↑Aspergillus precipitins
Itraconazole restarted
www.aspergillus.org.uk
Patient RWSeptember 1992
Chronic cavitary pulmonary Chronic cavitary pulmonary aspergillosisaspergillosis
www.aspergillus.man.ac.uk
Patient RWJune 2003
Underlying diseases in patients with CPA (%)
Smith, Eur Resp J 2011;37:865
Smith 0thers
Classical tuberculosis 17 31-81
Atypical tuberculosis 16 ?ABPA 14
12COPD/emphysema33 42-56
Pneumothorax17 12-17Lung cancer survivor 10
?Pneumonia 22 9-12Sarcoidosis (stage II/III) 7
12-17Thoracic surgery14 8-11Rheumatoid arthritis4 2
Asthma / SAFS 12 6-12
Ankylosing spondylitis 4 2-11
None1 15
Other problems and exacerbations
“Mrs Jones” with ABPA Superb
Good
Average
Poorly
Terrible
Time - Months and Years
Chest infection
Angina
Broken ankle ‘Flu and pneumonia
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 – check levels
• Amphotericin B and micafungin IV useful for failure of oral azole therapy
• Gamma IFN helpful in some cases
• Monitor for azole resistance
Cancer’s Origins Revealed
Link
Sanger Institute, Cambridge, UK
http://www.sanger.ac.uk/about/press/2013/130814.html
http://www.bbc.co.uk/news/health-23665996
Cancer Research
Scientists are reporting a significant milestone for cancer research after charting 21 major mutations behind the vast majority of tumours.
The disruptive changes to the genetic code, account for 97% of the 30 most common cancers.
Finding out what causes the mutations could lead to new treatments. Some, such as smoking are known, but more than half are still a mystery.
Consequences
Genomic sequencing of a person or family could tell us a lot about what their risk of which cancers is, what caused it and what we should do about it!
The same will be possible for aspergillosis – we just need a bit more time!
Manchester Fungal Infection Group (MFIG)
The University of Manchester has invested in building a world-leading research group to tackle a problem that is largely unrecognised yet affects millions of people each year.
Globally and annually, over 300 million people suffer from serious fungal infections, resulting in 1,350,000 deaths – many of which are unavoidable.
Most serious fungal infections are hidden, occurring as a consequence of other health problems such as asthma, AIDS, cancer or organ transplants. Delays or missed diagnosis often lead to death, serious chronic illness or blindness.
Manchester Fungal Infection Group (MFIG)
Now, the newly formed multidisciplinary Manchester Fungal Infection Group (MFIG) hopes to make a difference with the recruitment of three leading experts from Edinburgh and London.
Professor Nick Read has moved from Edinburgh University and leads the group, while Dr Elaine Bignell from Imperial College, London, has been appointed as a Reader, and Dr Mike Bromley as a lecturer. Manchester senior lecturers, Dr Paul Bowyer and Peter Warn will also join the MFIG and will work alongside the already thriving research and teaching teams of Professors David Denning and Malcolm Richardson, and Dr Riina Richardson, to form this pioneering Group.
Suggest a subject
Can be on any relevant subject you would like to hear our opinion or get our help with
Send suggestions to [email protected] notes to me at clinic or at the meetingPhone them in (24 hrs) at 0161 291 5866
Subjects
Mike Leach is there a half life to the aspergillus. if the anti fungal is working should there be a patterned reduction in IgE
Does aspergillus have a halflife?
Mike Leach is there a half life to the aspergillus? If the
anti fungal is working should there be a patterned reduction in IgE
I will assume Mike is talking about ABPA
Immune system
Our immune system has many parts that can correspond to several different waves of attack against infection Physical barriers (skin, mucus) Immediate non-specific (no memory) Adaptive (specific – provides immunity)
http://www.aspergillus.org.uk/newpatients/immune.php
IgE
Immunoglobulin E (IgE) – an antibodyAlso have IgA, IgG, IgM – each plays a
different role
IgE main role – defence against parasites!Normally very low levelsIgE is released as soon as an infection is
detected – the hypersensitivity response. Gets all immune cells ready for action – allergy!
IgE
IgE
Role in disease
People with lots of IgE circulating tend to be atopic – very sensitive to particular antigens (pollen, mould)
When stimulated triggers release of large amounts of histamine
Causes airway constriction, inflammation, runny nose eg hay fever
Once stimulus goes symptoms disappear as no more IgE made.
ABPA
Aspergillus permanently irritating sensitive lung tissue
IgE permanently stimulatedScarringWe can suppress IgE & histamine production
using steroid drugsAlso seem to be able to do it using antifungal
in many casesAnti – IgE drugs eg Xolair
Flare - up
Suspect some new tiny growth irritating lung ?Reaction to more moulds in the outside airOther infectionsOther IgE stimulating allergens
Steroid dose increased = fast relief=no new scarring
As we shut down IgE production patients feels better – measured IgE falls.
Usually use total IgE measurements but can do Aspergillus-specific IgE
Other Ig’s
Indicate infection rather than allergyWill cover this next month!
Thank You
“The best chance we have of beating this illness is to work together”
Living with it, Working with it, Treating it
Fungal Research Trust