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 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 Chronic cavitary pulmonary aspergillosis - RW September 1992 3 months are presenting with haemoptysis Aspergillus precipitins 3+ BAL – A. fumigatus July 1993 Denning DW et al, Clin Infect Dis 2003; 37:S265 Chronic cavitary pulmonary aspergillosis - RW July 1993 Bilateral fibrocystic sarcoidosis Pt AR, Feb 2003 Bilateral fibrocystic sarcoidosis Pre-existing cavities Pt AR, Feb 2004 Bilateral fibrocystic sarcoidosis, after 2 months of corticosteroids New cavity formation Pleural thickening Small aspergilloma Pt AR, April 2004 Bilateral fibrocystic sarcoidosis, 3 months later, off steroids – now chronic cavitary aspergillosis New cavity formation Larger aspergilloma Pt AR, July 2004 Chronic Cavitary Pulmonary Aspergillosis Normal 30 year female smoker Patient JA Jan 2001 Chronic Cavitary Pulmonary Aspergillosis Patient JA Feb 2002 Chronic Cavitary Pulmonary Aspergillosis Patient JA April 2003 Chronic Cavitary Pulmonary Aspergillosis Patient JA July 2003 Chronic pulmonary aspergillosis Infection of the lung by Aspergillus Single fungal ball or aspergilloma in a preexisting cavity Invasive aspergillosis /community acquired infection Chronic cavitary pulmonary aspergillosis +/- fungal ball Chronic fibrosing pulmonary aspergillosis +/- fungal ball Chronic cavitary pulmonary aspergillosis transforming to fibrosing aspergillosis July 2001, untreated Patient JP, June 1999 April 2003, untreated Denning DW et al, Clin Infect Dis 2003; 37(Suppl 3):S265-80 Progression of CCPA or regression? 2005 on AmB 2007 on no Rx 2010 still on no Rx Progression of CCPA or regression? 1992 1994 on no Rx 1997 still on no Rx Progression of CCPA or regression? Mar 2007 Dec 2005 Sept 2006 Development of chronic fibrosing pulmonary aspergillosis on therapy Chronic Cavitary Pulmonary Aspergillosis complicating ABPA Patient KM May 2004 ABPA exacerbation – patient VE August 2011 September 2011 ABPA exacerbation – patient AL May 2010 May 2011 June 2011 After prednisolone ABPA CT after exacerbation – patient AL May 2010 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; 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 Simple (single) aspergilloma Patient RK Haempotysis, nil else Positive Aspergillus antibodies in blood Lobectomy Wythenshawe Hospital Simple (single) aspergilloma Patient NM August 2006 May 2009 Community acquired New cough pneumonia requiring ICU care Positive Aspergillus antibodies in blood Lobectomy Wythenshawe Hospital 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 Treatment Antifungal therapy IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327 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 Fluid level Patient O’S Pre-aspiration Albumin 27 CRP 150 10mL thick pus aspirated under U/S Leucocytes +++, Bacterial culture negative A. fumigatus grown Wythenshawe Hospital 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 Allergic Bronchopulmonary Aspergillosis and Severe Asthma with Fungal Sensitisation Therapy of allergic aspergillosis IDSA guidelines. Walsh et al. Clin Infect Dis 2008;46:327 Therapy of allergic aspergillosis Knutsen et al. J All Clin Immunol In press Bronchiectasis complicating ABPA Wythenshawe Hospital ABPA and development of CPA 1985 1981 2002 1995 1993 www.aspergillus.org.uk CPA complicating ABPA – Patient MT 2008 2011 Denning et al, unpublished CPA complicating ABPA – Patient MT 2011 All new findings CPA complicating ABPA 3 patients with longstanding asthma and ABPA Note the pleural fibrosis with and without local cavitation Denning et al, unpublished Chest pain VA presented with significant right sided lateral chest pain. Underlying diagnosis of bronchiectasis What should you do? CT san sowing R sided bronchiectasis Isotope bone scan showing 2 rib fractures laterally Wythenshawe Hospital 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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