Management of Chronic Pulmonary Aspergillosis Chris Kosmidis, MD, PhD Consultant in Infectious Diseases Manchester University NHS Foundation Trust

Intended Learning Outcomes To be aware of the medical management of chronic pulmonary aspergillosis To understand the role and indications of intravenous antifungals in the management of CPA To be aware of the prognosis and predictors of poor outcomes in CPA

Principles of CPA management Oral azole therapy is key Therapy is long-term as relapse is common off therapy Itraconazole, voriconazole and posaconazole all effective Major drug interactions and common, serious side effects – drug level monitoring recommended IV Amphotericin B or echinocandins useful for failure of oral azole therapy Interferon-gamma supplementation helpful in some cases 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 Withdraw or minimise immunosuppressive drugs wherever possible, including inhaled steroids Monitor for azole resistance

Management of CPA CPA entity Initial therapy Duration Alternative therapy Cautions Simple aspergilloma Surgical resection .. None Sufficient respiratory reserve, relapse is possible Aspergillus nodule None, if asymptomatic Azole therapy, if progressive If multiple, continued imaging and possibly repeat biopsy if progressive Chronic cavitary and fibrosing CPA Itraconazole or voriconazole >6 months , typically long-term Posaconazole, Isavuconazole, liposomal amphotericin B, echinocandins Drug interactions, especially rifampicin; long-term toxicity include peripheral neuropathy and skin photosensitivity (voriconazole) Denning & Chakrabarti Lancet Infect Dis. 2017: S1473-3099(17)30309-2.

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 or asymptomatic Regression of Aspergilloma on treatment September , 2013 Aspergilloma September , 2016 No Aspergilloma

CPA management framework Itraconazole Voriconazole Posaconazole Isavuconazole IV Amphoterin B or echinocandins Key challenges Antifungal resistance Adverse events Drug-drug interactions

Response rate to antifungal therapy Itraconazole: 76.5% [6 mo]1 Voriconazole: 64% (3 mo )2, 32 % (6 mo)3 Posaconazole: 61% [6mo] vs 46% [12 mo]4 1Agarwal et al. Mycoses. 2013 Sep; 56(5):559-70 2Jain et al. J Infect. 2006 May; 52(5):e133-7. 3Cadranel et al . Eur J Clin Microbiol Infect Dis. 2012 Nov;31(11):3231-9. 4Felton et al. Clin Infect Dis. 2010 Dec 15;51(12):1383-91.

Response rate to antifungal therapy Micafungin and Voriconazole for CPA Response rate at 2-12 weeks Caspofungin: 47% Micafungin: 42% Micafungin and Voriconazole for CPA Response rate at 2 weeks Micafungin: 68% Voriconazole: 59% Response rate at 4 weeks Micafungin: 60% Voriconazole: 53% Kohno et al. J. Infect. 2010;61:410-8. Kohno et al. Eur J Clin Microbiol Infect Dis. 2013;32:387-97.

Itraconazole randomised clinical trial Oral itraconazole 6 mo 12 mo 35% 41% Stable Improved Standard care 6 mo 12 mo 23% 7% 29% 64% 71% 53% 21% 24% Deterioration 30% relapse off therapy in 6 months Natural history with no therapy over 12 months Agarwal et al 2013: Mycoses. 2013 Sep;56(5):559-70. doi: 10.1111/myc.12075. Epub 2013 Mar 18 31 patients: Randomised to Itraconazole (n=17) or no antifungal [supportive treatment only] (standard of care)(n=14): Overall response 76.5% vs. 35.7% (p=0.02) Response measure : Clinical or radiological , and overall Outcome: Clinical response was classified as improved, stable or worsened based on assessment of patient's sense of well-being, gain in weight, improvement in cough and exercise capacity, decrease in the number, and frequency and quantity of haemoptysis. Radiological response was considered present if there was decrease in the size/number of the fungal balls, attenuation of the paracavitary infiltrates or pleural fibrosis. The response was assessed objectively by measuring the longest diameter of various lesions and a 50% reduction was taken as criteria for improvement. Overall response was classified as: (a) improved: improved or stable clinical response and radiologically improved or stable disease; and (b) failed: worsening of symptoms or radiological progression. All outcomes were assessed at the end of 6 months of therapy. Follow up Patients were followed up for at least 6 months following completion of treatment. Agarwal R, et al, Mycoses. 2013 56:559-70.

Intravenous antifungals for CPA Amphotericin B or echinocandins Short-term course (2-4 weeks) Useful initial therapy in severe disease Symptomatic benefit may persist for weeks / months after completing course 3 – 4 courses per year can be given as a long – term management option Indications: Progressive disease Treatment failure on oral azoles Intolerance to triazoles Pan-azole resistance Infection control strategy (IV induction followed by an oral maintenance therapy ) Kohno et al J Infect 2010; 61: 410–418.

Outcome (survival) of treated CPA 1 Year 86% 5 Years 62% 10 Years 47% Lowes et al Eur Respir J. 2017;49:pii: 1601062

Recurrence (relapse) of CPA Relapse of CPA symptoms are common following discontinuation of long-term maintenance therapy. Relapse can be:- Clinical Worsening of clinical manifestations Radiological Enlargement of fungal balls or pre-existing cavities Serological Rising Aspergillus IgG titres Microbiological Strong PCR signals, culture positivity

Recurrence of CPA Predictors After medical treatment 41% (India) Agarwal et al. 2013 36% (Japan) Koyama et al 2014 17% (France) Cadranel et al 2012 11% (Italy) Cucchetto et al 2015 Post-surgical relapse 26% (UK) Farid et al 2013 3.9% (Seoul, S. Korea) Lee et al 2009 Predictors Younger age Bilateral or multilobar CPA disease Longer antifungal treatment duration Agarwal et al. Mycoses. 2013;56:559–70. Koyama et al. J Infect Chemother. 2014;20:375–9 Cadranel et al. Eur J Clin Microbiol Infect Dis. 2012;31:3231–9 Cucchetto et al. Infection. 2015;43:277–86. Farid et al J Cardiothorac Surg .2013;8:180. Lee et al. J Thorac Cardiovasc Surg . 2009;138:820–5

Prognostic factors Increased mortality is associated with:- Low body mass index NTM co-infection Underlying COPD Higher age Lower albumin Lower activity score in the St. George's Quality of Life score Bilateral aspergilloma >>aspergilloma Lowes et al Eur Respir J. 2017;49. pii: 1601062.

Summary Long-term oral triazole therapy is the mainstay for the management of chronic pulmonary aspergillosis Itraconazole, voriconazole and posaconazole are all effective IV Amphotericin B or echinocandins useful after failure of oral azole therapy Relapse of CPA symptoms are common following discontinuation of long-term maintenance therapy