Professor Denning summarises how we manage CPA at the National Aspergillosis Centre, what we have learned, what we are still learning. Graham Atherton describes IgE and how it affects Aspergillosis

1. LED BY GRAHAM ATHERTON
SUPPORTED BY
NAC CENTRE MANAGER CHRIS HARRIS
CPA AND THE USE OF ITRACONAZOLE
DAVID DENNING- DIRECTOR OF THE NATIONAL ASPERGILLOSIS CENTRE
NATIONAL ASPERGILLOSIS CENTRE
UHSM
MANCHESTER
Support Meeting for
Aspergillosis Patients & Carers
Fungal Research Trust

2. 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

3. Treating chronic pulmonary
aspergillosis – how do assess response
and what confuses us
David W. Denning
National Aspergillosis Centre,
University Hospital of South
Manchester
The University of Manchester

4. Different patterns of CPA
Radiological response varies by subtype of CPA

5. Chronic cavitary pulmonary aspergillosis
National Aspergillosis Centre
Chronic fibrosing pulmonary aspergillosis
Different patterns of CPA
Aspergillus nodule Simple aspergilloma

6. Simple (single) aspergilloma
Patient RK
Haempotysis,
nil else
Positive
Aspergillus
antibodies in
blood
Lobectomy
and cured
Howard et al. Mycoses 2013;56:434

7. 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

8. 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 symptoms
Prevent further haemoptysis (coughing blood)
Stop progression of scarring in the lung
Prevent the emergence of antifungal resistance
Avoid antifungal toxicity
Patients with few symptoms
Stop progression of scarring in the lung
Prevent the emergence of antifungal resistance
Avoid antifungal toxicity

9. 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/d
107 patients with CPA
2-4 weeks treatment

10. Felton, Clin Infect Dis 2010; 51:1383.

11. CPA and voriconazole Rx
Camuset et al, Chest 2007:131:1435
9 patients with chronic cavitary pulmonary aspergillosis
15 with chronic necrotising pulmonary aspergillosis
13/24 (54%) primary therapy with voriconazole
3 intolerant of voriconazole
Median duration of Rx 6.4 mos (4-36)

12. Time to initial response with posaconazole
therapy
6 months 12 months
Mean
95% confidence interval
Felton et al. Clin Infect Dis 2010; 51:1383

13. 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.

14. 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
PosaconazoleVoriconazoleItraconazole
n= 25 23 7n= 24 24 15n= 19 16 12
ImprovedStableDeteriorated

15. Progression of CCPA
1992 1994 on no Rx 1997 still on no Rx

16. 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

17. Chronic cavitary pulmonary aspergillosis –
CT reconstruction
Wythenshawe Hospital

18. Aspergillus IgG in blood
Falling levels is good, but takes months or years

19. Bilateral fibrocystic sarcoidosis – no symptoms
Pt AR, Feb 2004
Pre-existing cavities

20. Bilateral fibrocystic sarcoidosis, after 2
months of prednisolone
Pt AR, April 2004
Pleural thickening
Small aspergilloma
New cavity
formation

21. Treated with prednisolone - 3 months later, off
steroids – now chronic cavitary aspergillosis
Pt AR, July 2004
Larger aspergilloma
New cavity
formation

22. Chronic cavitary pulmonary aspergillosis -
an example of radiographic failure
Patient SS
April 2004
www.aspergillus.org.uk
Patient SS
July 2004, despite receiving
itraconazole for 3 months

23. 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%
Deterioration
30% 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.

24. 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

25. 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

26. Patient RW
September 1992
Chronic cavitary pulmonary aspergillosisChronic cavitary pulmonary aspergillosis
www.aspergillus.man.ac.uk
Patient RW
June 2003

27. 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
12
COPD/emphysema 33
42-56
Pneumothorax 17
12-17
Lung cancer survivor 10
?
Pneumonia 22

28. 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

29. 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

30. Cancer’s Origins Revealed

31. Link
Sanger Institute, Cambridge, UK
http://www.sanger.ac.uk/about/press/2013/130814.html
http://www.bbc.co.uk/news/health-23665996

32. 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.

33. 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!

34. 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.

35. 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.

36. Suggest a subject
Can be on any relevant subject you would like to hear
our opinion or get our help with
Send suggestions to admin@aspergillus.org.uk
Pass notes to me at clinic or at the meeting
Phone them in (24 hrs) at 0161 291 5866

37. 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

38. 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

39. 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/immun
e.php

40. IgE
Immunoglobulin E (IgE) – an antibody
Also have IgA, IgG, IgM – each plays a different role
IgE main role – defence against parasites!
Normally very low levels
IgE is released as soon as an infection is detected –
the hypersensitivity response. Gets all immune cells
ready for action – allergy!

41. IgE

42. IgE

43. 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.

44. ABPA
Aspergillus permanently irritating sensitive lung
tissue
IgE permanently stimulated
Scarring
We can suppress IgE & histamine production using
steroid drugs
Also seem to be able to do it using antifungal in
many cases
Anti – IgE drugs eg Xolair

45. Flare - up
Suspect some new tiny growth irritating lung ?
Reaction to more moulds in the outside air
Other infections
Other 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

46. Other Ig’s
Indicate infection rather than allergy
Will cover this next month!

47. 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