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Disease progression and approaches to therapy

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

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Disease progression and approaches to therapy

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  1. Disease progression and approaches to therapy David W. Denning Director, National Aspergillosis Centre University Hospital South Manchester [Wythenshawe Hospital] The University of Manchester

  2. Chronic Pulmonary Aspergillosis

  3. 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

  4. July 1993 Chronic cavitary pulmonary aspergillosis - RW September 1992 3 months are presenting with haemoptysis Aspergillus precipitins 3+ BAL – A. fumigatus Denning DW et al, Clin Infect Dis 2003; 37:S265

  5. Chronic cavitary pulmonary aspergillosis - RW July 1993

  6. Bilateral fibrocystic sarcoidosis Pt AR, Feb 2003

  7. Bilateral fibrocystic sarcoidosis Pre-existing cavities Pt AR, Feb 2004

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

  9. Bilateral fibrocystic sarcoidosis, 3 months later, off steroids – now chronic cavitary aspergillosis New cavity formation Larger aspergilloma Pt AR, July 2004

  10. Chronic Cavitary Pulmonary Aspergillosis Normal 30 year female smoker Patient JA Jan 2001

  11. Chronic Cavitary Pulmonary Aspergillosis Patient JA Feb 2002

  12. Chronic Cavitary Pulmonary Aspergillosis Patient JA April 2003

  13. Chronic Cavitary Pulmonary Aspergillosis Patient JA July 2003

  14. Chronic pulmonary aspergillosis Infection of the lung by Aspergillus Single fungal ball or aspergilloma in a pre-existing cavity Invasive aspergillosis /community acquired infection Chronic cavitary pulmonary aspergillosis +/- fungal ball Chronic fibrosing pulmonary aspergillosis +/- fungal ball

  15. Chronic cavitary pulmonary aspergillosis transforming to fibrosing aspergillosis July 2001, untreated April 2003, untreated Patient JP, June 1999 Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80

  16. Progression of CCPA or regression? 2005 on AmB 2010 still on no Rx 2007 on no Rx

  17. Progression of CCPA or regression? 1994 on no Rx 1992 1997 still on no Rx

  18. Mar 2007 Progression of CCPA or regression? Dec 2005 Sept 2006 Development of chronic fibrosing pulmonary aspergillosis on therapy

  19. Chronic Cavitary Pulmonary Aspergillosis complicating ABPA Patient KM May 2004

  20. ABPA exacerbation – patient VE August 2011 September 2011

  21. ABPA exacerbation – patient AL May 2010 June 2011 After prednisolone May 2011

  22. ABPA CT after exacerbation – patient AL May 2010

  23. 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;

  24. 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

  25. Simple (single) aspergilloma Patient RK Haempotysis, nil else Positive Aspergillus antibodies in blood Lobectomy Wythenshawe Hospital

  26. Simple (single) aspergilloma Patient NM Positive Aspergillus antibodies in blood Lobectomy August 2006 May 2009 Community acquired New cough pneumonia requiring ICU care Wythenshawe Hospital

  27. 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

  28. Treatment

  29. Antifungal therapy IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

  30. 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

  31. Fluid level Patient O’S Pre-aspiration 10mL thick pus aspirated under U/S Albumin 27 CRP 150 Leucocytes +++, Bacterial culture negative A. fumigatus grown Wythenshawe Hospital

  32. 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

  33. Allergic Bronchopulmonary Aspergillosis and Severe Asthma with Fungal Sensitisation

  34. Therapy of allergic aspergillosis IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327

  35. Therapy of allergic aspergillosis Knutsen et al. J All Clin Immunol In press

  36. Bronchiectasis complicating ABPA Wythenshawe Hospital

  37. 1985 1995 1981 2002 1993 ABPA and development of CPA www.aspergillus.org.uk

  38. CPA complicating ABPA – Patient MT 2008 2011 Denning et al, unpublished

  39. CPA complicating ABPA – Patient MT 2011 All new findings

  40. CPA complicating ABPA3 patients with longstanding asthma and ABPANote the pleural fibrosis with and without local cavitation Denning et al, unpublished

  41. Chest pain VA presented with significant right sided lateral chest pain. Underlying diagnosis of bronchiectasis What should you do? Isotope bone scan showing 2 rib fractures laterally CT san sowing R sided bronchiectasis Wythenshawe Hospital

  42. 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

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