Management of Chronic Pulmonary Aspergillosis and IgE for the Layperson

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Professor Denning summarises how we manage CPA at the National Aspergillosis Centre, what we have learned, what we are still learning. …

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

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  • Mean + 95% CI

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  • 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