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 admin@aspergillus.org.ukPass 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