Slide repository module 1 - Introduction

1. Non-tuberculous mycobacterial lung disease (NTM-LD) and bronchiectasis slide repository Slide repository module 1 - Introduction

2. Objectives What is the purpose of this slide repository and how can it be used? • This slide repository is intended to serve as comprehensive educational resource, inter alia for pulmonologists, microbiologists, radiologists, pharmacists and others who are involved in the management and treatment of patients with NTM-LD and bronchiectasis across Europe • This educational resource comprises more than 200 slides for educational purposes, including the use in educational meetings Which data sources were used to create this repository? • The slide collection is based on published literature complemented by the authors and their recommendations from clinical practice • The slide repository is a living document, which will need to be updated and complemented with emerging data as these become available NTM-LD, non-tuberculous mycobacterial lung disease.

3. Date of preparation and support When was the slide repository released? • The current version of the slide repository was released during May 2018 Who was involved in preparation of the slide repository? • The slide repository was developed by a multidisciplinaryEuropean scientific committee • The development of this slide repository by the multidisciplinary European scientific committee was facilitated by Physicians World Europe GmbH and funded by Insmed

4. MultidisciplinaryEuropean scientific committee • Stefano Aliberti, Respiratory Physician University of Milan, Italy • Claire Andrejak, Pulmonologist CHU Amiens-Picardie, Amiens, France • James Chalmers, Respiratory Physician Ninewells Hospital, Dundee, UK • Jakko van Ingen, Clinical Microbiologist Radboud University Medical Centre, Nijmegen, TheNetherlands • Gianluca Milanese, Radiologist University of Parma, Italy • Eva Polverino, Pulmonologist, expert in respiratory infections Vall d’Hebron University Hospital, Barcelona, Spain • Dirk Wagner, Infectious disease expert University of Freiburg Medical Centre, Germany

5. Slide repository table of contents • Module 1 Introduction • Module 2 Non-tuberculous mycobacteria (NTM) • Module 3 NTM-LD and bronchiectasis • Module 4 NTM-LD and COPD • Module 5 Diagnosis of NTM-LD • Module 6 Management of NTM-LD • A summary and glossary can be found at the end of each module COPD, chronic obstructive pulmonary disease; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease.

6. Detailed table of contents: Module 2 - Non-tuberculous mycobacteria (NTM) Epidemiology • Distribution of respiratory NTM isolates varies between geographical regions • Prevalence of NTM-LD is underestimated • Increasing diagnosis of NTM-LD • Why are the rates of NTM infections increasing? • Estimating NTM-LD numbers – an ongoing challenge Impact of disease • Quality of life is significantly reduced in patients with NTM-LD • NTM-LD can be a progressive, and ultimately lethal, lung disease • Increasing hospitalization rate for NTM-LD • Survival time correlates with the causative NTM species • Mortality in high-risk patients with NTM-LD (1) • Mortality in high-risk patients with NTM-LD (2) • Higher mortality with cavitary disease Summary Glossary • Milestones in NTM research • What are NTM? • NTM vs. Mycobacterium tuberculosis: Key distinctions • NTM classification • NTM are found throughout the environment • Transmission of NTM • The hydrophobic outer membrane supports NTM survival and distribution Risk factors for NTM-LD • Not all NTM are equal (1) • Not all NTM are equal (2) • NTM disease: 4 main manifestations • Nodular/bronchiectatic and fibrocavitary disease – the two forms of NTM-LD • Host risk factors – nodular/bronchiectatic NTM-LD • Host risk factors – fibrocavitary NTM-LD • Environmental risk factors for NTM-LD • Genetic and iatrogenic factors associated with NTM-LD • NTM-LD is associated with multi-system diseases • The pattern of disease recognition has changed over time • Bronchopulmonary factors associated with NTM-LD • Most common bronchopulmonary factors associated with NTM-LD • Trends of associated diagnoses in hospitalized patients with NTM-LD between 2005 and 2011 NTM and disease • NTM organisms commonly isolated from the respiratory tract • Diagnosis and management of NTM-LD are challenging NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease.

7. Detailed table of contents: Module 3 - NTM-LD and bronchiectasis • Overall prevalence of NTM isolation in patients with bronchiectasis- a “first meta-analysis” • Bronchiectasis and NTM • EMBARC: The European Bronchiectasis Registry Treatment of bronchiectasis • A general overview on bronchiectasis management • Treatment of bronchiectasis • Treatment principles for bronchiectasis • When to look for NTM in patients with bronchiectasis • Guidelines about sputum induction • Guidelines about sputum processing Managing exacerbations of bronchiectasis • Indication of antibiotic treatment in case of exacerbations according to the BTS guidelines • Indication of antibiotic treatment in case of exacerbations according to the SEPAR guidelines • ERS recommendations for long-term antibiotic treatment of bronchiectasis • Macrolide therapy reduces pulmonary exacerbations • Eradication therapy for Pseudomonas aeruginosa infections • Possible and alternative eradication treatment pathways for Pseudomonas aeruginosa infections • Macrolide therapy of bronchiectasis: Avoiding antibiotic resistance Other treatment options for bronchiectasis • The role of neutrophil elastase inhibitors in lung diseases • Treatment comments for NTM in bronchiectasis Summary Glossary Development of bronchiectasis and pathophysiology • Pathophysiology and clinical presentation of bronchiectasis • Pathophysiology: Vicious Cycle hypothesis • Inflammation in bronchiectasis • Bronchiectasis: What happens to the lungs on a macro level? • Bronchiectasis: Clinical Manifestation • Bronchiectasis is a heterogeneous disease • Mortality associated with bronchiectasis • Risk factors for increased mortality • Bronchiectasis scores can be used to classify disease severity • Value of comorbidities on bronchiectasis severity and mortality - Bronchiectasis Aetiology Comorbidity Index (BACI) Diagnosis of bronchiectasis • Diagnosis of bronchiectasis: Key concepts • Diverse conditions and symptoms are associated with bronchiectasis: BTS and SEPAR guidelines • Heterogeneity of bronchiectasis • Common symptoms and signs of bronchiectasis • Symptoms of bronchiectasis exacerbations • Aetiological diagnosis of bronchiectasis • Warning signs to suspect bronchiectasis • Characteristics of bronchiectasis - high resolution CT • Three main radiological categories for bronchiectasis NTM and bronchiectasis • Radiographic Diagnosis: NTM in bronchiectasis - HRCT • NTM in bronchiectasis pathophysiology: Chicken or egg? • Host risk factors for NTM-LD • High prevalence of NTM isolation in patients with bronchiectasis BACI, Bronchiectasis Aetiology Comorbidity Index; BTS, British Thoracic Society; COPD, chronic obstructive pulmonary disease; CT, computed tomography; EMBARC, European multicentre bronchiectasis audit and research collaboration; ERS, European Respiratory Society; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease; SEPAR, Spanish Society of Pneumology and Thoracic Surgery.

8. Detailed table of contents: Module 4 - NTM-LD and COPD • COPD Epidemiology • COPD – Definition, symptoms, risk factors • COPD – Diagnosis • Smoking increases the risk of COPD, and smoking cessation can reduce the rate of lung function decline • GOLD 2017: Symptoms and exacerbation risk should be assessed to determine appropriate treatment • A revised approach to treatment recommendations • COPD – The Current Categories • Pathogenesis of chronic lung disease – the Dutch hypothesis • COPD Pathogenesis (I) • COPD Pathogenesis (II) • COPD: Clinical findings • Prevalence of COPD in patients with NTM-LD • Patients with COPD and NTM-LD are more likely to have fibrocavitary disease • Andrejak et al: Odds of Developing NTM in various Respiratory Conditions • Andrejak et al: Odds of Developing NTM in patients with COPD according to ICS use • Prevalence of concurrent clinically unexpected NTM infection in patients with severe COPD • NTM isolation is associated with lung function decline in COPD Summary (1) Summary (2) Glossary COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroids; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease.

9. Detailed table of contents: Module 5 - Diagnosis of NTM-LD • The patient journey is typically long and difficult before diagnosis -Only a few are diagnosed correctly from the outset Diagnosis • Symptoms of NTM-LD are frequently non-specific • Diagnostic criteria: Clinical, radiographic, and microbiologic criteria must be met to make a diagnosis of NTM-LD • Diagnosis of NTM-LD • Diagnostic criteria for NTM-LD • Radiographic criteria • Radiographic criteria: Nodular/bronchiectatic form • Radiographic criteria: Fibrocavitary form • Radiographic criteria: Hypersensitivity-like pneumonitis • Microbiologic criteria: Culture of NTM essential for diagnosis • Potential for contamination of samples • Drug susceptibility testing in NTM • Species-level identification of NTM is clinically important • NTM-LD and TB must be differentiated • Pulmonary TB and NTM-LD: Comparison of radiographic findings • Colonisation Summary Glossary NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease; TB, tuberculosis.

10. Detailed table of contents: Module 6 - Management of NTM-LD (I) • Patients with microscopically positive MAC-LD show a faster disease progress • NTM-LD: Pathogens and pathogenic factors to consider • Antibiotic therapy: To treat or not to treat – that is the question • Anti-infective agents – Classification based on target site of action • Macrolides: clarithromycin, azithromycin • Ethambutol • Rifamycins • Aminoglycosides • Other drugs used for treatment of NTM-LD (1) • Other drugs used for treatment of NTM-LD (2) • ATS/IDSA treatment recommendation for nodular/bronchiectatic MAC-LD (not severe, initial therapy) • ATS/IDSA treatment recommendation for fibrocavitary and severe or previously treated nodular/bronchiectatic MAC-LD • MAC-LD: Antibiotic therapy (summary) • Refractory MAC-LD: Antibiotic therapy • Case series on MAC-LD • NTM-LD in patients with cystic fibrosis: Antibiotic therapy • M. abscessus lung disease: Antibiotic therapy • Case series on M. abscessus disease • Monitoring for antimycobacterial drug-related toxicity • Oral drug administration – considerations • Intravenous drug administration - considerations • Inhalation - considerations Treatments in development and trials in progress for NTM • Ongoing trials and treatments at development stage Multidisciplinary management of NTM-LD • A multidisciplinary approach is required for NTM-LD management • Role of the pharmacist in managing patients with NTM-LD Treatment • First steps in managing NTM-LD – Disease characteristics • First steps in managing NTM-LD – Treatment considerations • Guidance for therapy decisions • ATS/IDSA treatment recommendations • MAC-LD: Consideration of disease severity • MAC-LD therapy in EU5: Treatment guidelines vs. reality • MAC-LD therapy in the US: Treatment guidelines vs. reality • Association between adherence to ATS/BTS treatment guidelines (1997/1999) and outcome • NTM-LD therapy • Adjunctive therapies for patients with bronchiectasis according to BTS guidelines Entry of drugs and bugs into the macrophage • NTM pathogenesis: Gaining entry • NTM pathogenesis: Defense vs. offense in the macrophage • The journey of the drug – routes of administration (1) • The journey of the drug – routes of administration (2) • The bloodstream – examples in NTM-LD • How NTM drugs reach the site of infection – The final entry into the macrophage NTM-LD and antibiotic therapies • Survival time correlates with the causative NTM species • Higher mortality with cavitarydisease ATS, American Thoracic Society;BTS, British Thoracic Society; EU5, European Union Five (France, Germany, Italy, Spain, United Kingdom); IDSA, Infectious Diseases Society of America; MAC-LD, Mycobacterium avium complex lung disease; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease.

11. Detailed table of contents: Module 6 - Management of NTM-LD (II) Drug susceptibility testing • Drug susceptibility testing for NTM • Drug susceptibility testing for MAC and M. abscessus • Drug susceptibility testing for NTM Surgery • Surgical treatment of NTM-LD • Indications for surgical treatment of NTM-LD caused by MAC or M. abscessus Treatment goals and monitoring • NTM-LD: Three potential treatment goals • Goals of therapy: Symptomatic, microbiologic • Unmet needs in NTM-LD • Antibiotic resistance in MAC-LD – an unmet need • The problem of macrolide resistance • Treatment success in patients with or without macrolide resistance • Failure of therapy in MAC-LD – an unmet need • Reinfection in MAC-LD – an unmet need Summary Glossary MAC, Mycobacterium aviumcomplex; MAC-LD, Mycobacterium avium complex lung disease; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease.