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Slide repository module 2

Non-tuberculous mycobacteria (NTM). Slide repository module 2. Development of the slide repository and financial support. The slide repository was developed by a multidisciplinary European scientific committee: Stefano Aliberti , Respiratory Physician University of Milan, Italy

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Slide repository module 2

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  1. Non-tuberculous mycobacteria (NTM) Slide repository module 2

  2. Development of the slide repository and financial support • The slide repository was developed by a multidisciplinaryEuropean scientific committee: • Stefano Aliberti, Respiratory Physician University of Milan, Italy • Claire Andrejak, Pulmonologist CHU Amiens-Picardie, Amiens, France • James Chalmers, Respiratory Physician NinewellsHospital, Dundee, UK • Jakko van Ingen, Clinical Microbiologist RadboudUniversity Medical Centre, Nijmegen, The Netherlands • 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 • The development of this slide repository by the multidisciplinary European scientific committee was facilitated by Physicians World Europe GmbH and funded by Insmed

  3. Milestones in NTM research Robert Koch discovers Mycobacterium tuberculosis1 Nodular/bronchiectatic disease identified and named “Lady Windermere syndrome”5 Sporadic case reports;strains named Battey, Ryan, Mx etc.3 ATS/IDSA guidelines: Definition of NTM-LD, diagnosis and treatment recommendations7 1880 1900 1920 1940 1960 1980 2000 2010 2020 • “Atypical M. tuberculosis” identified in birds, reptiles, fish and the environment1-3 Buhler and Pollak isolate M. kansasii from patients with cavitary disease4 Disseminated M. avium disease identified in HIV/AIDS patients6 AIDS, acquired immune deficiency syndrome; ATS, American Thoracic Society; HIV, human immunodeficiency virus; IDSA, Infectious Diseases Society of America; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease. 1. Johnson MM, Odell JA. J Thorac Dis 2014; 6:210-20; 2. Aronson JD. The Journal of Infectious Diseases 1926; 39:315-20; 3. personal communication by scientific committee; 4. Buhler VB, Pollak A. Am J Clin Pathol 1953; 23:363-74; 5. Reich JM, Johnson RE. Chest 1992; 101:1605-9; 6. Horsburgh 1999 J Infect Dis 179 Suppl 3 S461-5; 7. Griffith ED, et al. Am J Respir Crit Care Med 2007; 175:367-416.

  4. What are NTM? • NOT assigned to either:1,2 • Mycobacterium tuberculosis complex • Mycobacterium leprae • Also known as:2 • Environmental mycobacteria • Opportunistic mycobacteria • Atypical mycobacteria • Mycobacteria other than tuberculosis (MOTT) NTM • Recognition: • Identified soon after M. tuberculosis, not initially recognized as pathogenic2 • Suspected as potential cause of human infections in the sanatorium era4 • 1950s: Direct evidence for causation of disease4 • Opportunistic infections in HIV patients led to wider recognition & investigation4 • Characteristics: • Found in the environment1,2 • Opportunistic pathogens of humans & animals3 • As of 2015: > 172 different species with distinct virulence features3 HIV, human immunodeficiency virus; MOTT, mycobacteria other than tuberculosis; NTM, non-tuberculous mycobacteria. 1. McShane PJ, Glassroth J. Chest 2015; 148:1517-27; 2. Schönfeld N, et al. Pneumologie 2013; 67:605-33; 3. Faria S, et al. J Pathog 2015; 2015:809014; 4. Orme IM, Ordway DJ. Infect Immun 2014; 82:3516-22.

  5. NTM vs. Mycobacterium tuberculosis: Key distinctions NTM and Mycobacterium tuberculosis differ in terms of pathogenicity, infection rates and transmission routes NTM, non-tuberculous mycobacteria. 1. Primm TP, et al. Clin Microbiol Rev 2004; 17:98-106; 2. Tortoli E. Clin Microbiol Infect 2009; 15:906-10; 3. Tortoli E. FEMS Immunol Med Microbiol 2006; 48:159-78; 4. McShane PJ, Glassroth J. Chest 2015; 148:1517-27; 5. Brode SK, et al. Int J Tuberc Lung Dis 2014; 18:1370-7; 6. Van Soolingen D. J Intern Med 2001; 249:1-26; 7. Cole ST. Microbiology 2002; 148:2919-28.

  6. NTM classification1 Growth rate Rapid (usually 7-10 days2) Slow (usually 1-3 weeks, sometimes up to 8 weeks2) M. kansasii M. terrae M. celatum M. tuberculosis M. avium M. abscessus M. fortuitum M. smegmatis M. simiae gastri gordonae kansasii kubicae mar.Europe kyorinense celatum marinum M shimoldei marinum M82 fragae liflandii xenopi RIVM ulcerans xenopi szulgai hiberniae riyadhense engbaekii lacus nonchrom. longobard. leprae Br49 sinense leprae TN senuense can. 70010 terrae can. 70008 triviale can. 60008 rhodes. JS60 tuberc gilvum Spyr1 tuberc. H37R gilvum PYR tuberc. KZN iranicum africanum vaccae orygis vanbaalenii bovis chubuense bovis Mexico sp. KMS bovis Tokyo sp. MCS conspicuum sp. JLS sherrisii doricum triplex thermores. hassiacum florentinum phlei palustre tusciae sp. IEC1808 rhodes. NBB3 interjectum smeg. JS623 para. IEC26 peregrinum para. 07156 fortuitum para. 10043 conception. mageritense parmense sp. 141 bohemicum sp. 155 saskatch. wolinskyi parascrof. smeg. MC2 europaeum canariasense nebraskense sp. 360MFT avium confluentis avium K10 fallax avium MAP4 absc. G006 colombiense absc. 5094 chimaera abscessus yongonense immunogen intrac. 13950 chelonae intrac. 02 A. subflavus intrac. 64 ind. pranii NTM, non-tuberculous mycobacteria. 1. Fedrizzi T, et al. Sci Rep 2017; 7:45258; 2. Thomson 2009 Respirology 14 (1), 12-26. Figure adapted from Fedrizzi T, et al. Sci Rep 2017; 7:45258

  7. NTM are found throughout the environment Natural water sources Drinking water distribution systems (biofilm formation) Hot tubs and spas Acidic, brown-water swamps Potting soils Boreal forest soils and peats Metal removal fluid systems NTM habitats are intimately shared with those of humans NTM, non-tuberculous mycobacteria. Falkinham JO, 3rd. J Appl Microbiol 2009; 107:356-67; pictures taken from https://pixabay.com/.

  8. Transmission of NTM Inhalation of NTM-laden aerosols or dust1 Ingestion of soil or water1 • Gastroesophageal reflux disease has been indicated as a mediator of NTM-LD1 • Swallowing of NTM followed by gastric reflux leading to aspiration into the lung Likely routes of infection Person-to-person transmission extremely rare, but some evidence of this in the CF community3 Contamination of hospital water supplies and medical equipment2 CF, cystic fibrosis; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease1. Falkinham JO, 3rd. J Appl Microbiol 2009; 107:356-67; 2. Johnson MM, Odell JA. J Thorac Dis 2014; 6:210-20; 3. McShane PJ, Glassroth J. Chest 2015; 148:1517-27.

  9. The hydrophobic outer membrane supports NTM survival and distribution Lipopolysaccharide • Promotes surface attachment and biofilm formation • Prevents wash-out Mycolic acid Cell wall Peptidoglycan/arabinanlayer • Protects against antimicrobial agents, including antibiotics and disinfectants Plasma membrane Protein • Concentrates bacteria at air/water interface • Aids aerosol distribution and transmission from water distribution systems by inhalation Mycobacterium Biofilm formation and hydrophobic characteristics allow colonisationof unfavourable habitats and easy spread NTM, non-tuberculous mycobacteria. Falkinham JO, 3rd. J Appl Microbiol 2009; 107:356-67.

  10. Risk factors for NTM-LD

  11. Not all NTM are equal (1) Clinical relevance is different for each NTM species1–3 M. intracellulare M. malmoense M. abscessus M. genavense M. gordonae M. chimaera M. chelonae M. fortuitum M. kansasii M. celatum M. szulgai M. xenopi M. avium M. simiae 0% 100% 25% 50% 75% (% of patients who met diagnostic criteria, per species) NTM, non-tuberculous mycobacteria. 1. van Ingen J, et al. Thorax 2009; 64:502-6; 2. van Ingen J, et al. Infect Genet Evol 2012; 12:832-7; 3. Zweijpfenning S, et al. Respir Med 2017; 131:220-4.

  12. Not all NTM are equal (2) NTM-LD frequency according to NTM species (N=104) Cases (n) 15 M. kansasii 15 4 11 M. xenopi 15 = disease 8 5 3 M. malmoense = no disease M. avium/ M. intracellulare 29 22 51 M. fortuitum/ M. chelonae 1 4 5 10 10 M. gordonae % NTM species isolated from pulmonary samples vary in virulence: Isolation of M. kansasii often correlates with disease NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease. Adapted from Schönfeld N, et al. Pneumologie 2013; 67:605-33.

  13. NTM disease: 4 main manifestations Pulmonary disease1,2 Lymphatic disease1,2 Predisposing lung conditions1,3 Predisposing genetic factors4 Situational (hypersensitivity pneumonitis)2,3 The lung is by far the most frequent disease site1 Typically an infantile disease affecting cervical lymph nodes2 Also in adults with HIV infection1 Skin/soft tissue disease1,2 Disseminated disease1,2 • The most common sources include: • contact with contaminated water or infected fish2 • traumas and surgical wounds2 • Nosocomial infections have been described3 Most commonly seen in association with profound immunosuppression, e.g. HIV infection2,3 Both host factors and organism characteristics influence the susceptibility and manifestations of NTM disease3 HIV, human immunodeficiency virus; NTM, non-tuberculous mycobacteria. 1. Griffith DE, et al. Am J Respir Crit Care Med 2007; 175:367-416; 2. Tortoli E. Clin Microbiol Infect 2009; 15:906-10; 3. Johnson MM, Odell JA. J Thorac Dis 2014; 6:210-20; 4. McShane PJ, Glassroth J. Chest 2015; 148:1517-27.

  14. Nodular/bronchiectatic and fibrocavitary disease – the two forms of NTM-LD • Epidemiology • Postmenopausal females1 • Scoliosis, mitral valve prolapse, low BMI1,2 • No pre-existing lung disease2 • Clinical course • Prolonged cough, fatigue, weight loss1 • Microbiology (classical) • Low yield of Ziehl-Neelsen positive sputum culture - should repeat or use BAL4 • Radiology • Bronchiectasis with nodules “tree-in-bud” appearance1 • Middle lobe and lingula worst affected1,2 Nodular/bronchiectatic“Lady Windermere syndrome” • Epidemiology • Mostly males1 • Middle-aged (late 40s-early 50s)1 • Pre-existing COPD, silicosis, fibrosis3 • Clinical course • Tuberculosis-like, but slower4 • Microbiology (classical) • Often Ziehl-Neelsen positive sputum4 • High yield of culture4 • Radiology • Fibro-cavitary lesions, upper lobes3 Fibrocavitary BAL, bronchoalveolar lavage; COPD, chronic obstructive pulmonary disease; NTM-LD, non-tuberculous mycobacterial lung disease. 1. Griffith DE, et al. Am J Respir Crit Care Med 2007; 175:367-416; 2. Kim RD, et al. Am J Respir Crit Care Med 2008; 178:1066-74; 3. Johnson MM, Odell JA. J Thorac Dis 2014; 6:210-20; 4. personal communication by scientific committee.

  15. Host risk factors – nodular/bronchiectatic NTM-LD Body morphotype of patients with active NTM infection compared with healthy controls1 Female patients (n=60) Matched control subjects* 161.0 cm (Height) 164.7 cm* (Height) • Lean and tall stature1 • Low BMI1,2 • Skeletal abnormalities1,2 • Scoliosis • Pectus excavatum • Mitral valve prolapse1 • Among Caucasians, women have a higher prevalence than men3 28.2 (BMI) 21.1 (BMI) 95.1 cm (Waist) 74.2 cm* (Waist) 57.2 kg* (Weight) 73.1 kg (Weight) There is an association between nodular/bronchiectatic NTM-LD and a particular body habitus – predominantly in postmenopausal women1,4 *NHANES age- and ethnicity-matched female control subjects (2001-2002 data).BMI, Body-Mass-Index; NTM, non-tuberculous mycobacteria; NTM-LD, non‑tuberculous mycobacterial lung disease. 1. Adapted from Kim RD, et al. Am J Respir Crit Care Med 2008; 178:1066-74; 2. Dirac MA, et al. Am J Respir Crit Care Med 2012; 186:684-91; 3. Adjemian J, et al. Am J Respir Crit Care Med 2012; 185:881-6; 4. Griffith DE, et al. Am J Respir Crit Care Med 2007; 175:367-416.

  16. NTM-LD is associated with multi-system diseases • Cilia genes, needed for mucociliary clearance e.g. RSPH11 • Connective tissue genes1,2 • Immune-related genes, e.g. STAT11 • CFTR mutation, resulting in thickened mucus1,2 CFTR, cystic fibrosis transmembrane conductance regulator; NTM-LD, non-tuberculous mycobacterial lung disease; RSPH1, Radial spoke head 1 homolog; STAT1, Signal transducer and activator of transcription 1.1. Szymanski EP, et al. Am J Respir Crit Care Med 2015; 192:618-28; 2. McShane PJ, Glassroth J. Chest 2015; 148:1517-27.

  17. Host risk factors – fibrocavitary NTM-LD ♂ • Structural lung disease e.g. COPD, silicosis or prior tuberculosis2 • Males in their late 40s and early 50s1 • History of cigarette smoking • Often, excessive alcohol use1 Fibrocavitary NTM-LD commonly occurs in older males, often smokers, with a history of underlying lung disease1,2 COPD, chronic obstructive pulmonary disease; NTM-LD, non-tuberculous mycobacterial lung disease. 1. Griffith DE, et al. Am J Respir Crit Care Med 2007; 175:367-416; 2. Johnson MM, Odell JA. J Thorac Dis 2014; 6:210-20.

  18. Environmental risk factors for NTM-LD Areas in the United States* with a high risk for a NTM-LD infection • Socioeconomic and environmental risk factors include: • Greater population density • Higher education and income • High evapotranspiration and percentages covered by surface water *US study chosen due to high number of unique cases: Nearly 2.3 million individuals from all 50 states and the District of Columbia were included, from which 16,508 NTM-LD claims representing 2,548 unique cases were identified. Data are representative but not directly applicable to the European situation. NTM-LD, non-tuberculous mycobacterial lung disease. Adapted from Adjemian J, et al. Am J Respir Crit Care Med 2012; 186:553-8.

  19. Genetic and iatrogenic factors associated with NTM-LD Genetic predisposition Iatrogenic factors • Potentially a multigenic disease1 • Mutation in CFTR gene1,2 • Other mutations including immune factors, cilia genes and connective tissue genes1,2 • Familial clustering of NTM-LD3 • Majority of cases in non‑smoking siblings with high prevalence of scoliosis and CFTR mutations3 • Immunosuppressive treatments associated with NTM-LD include: • COPD patients treated with inhaled corticosteroids (adjusted OR 19.6; 95% CI 9.7–39.6)4 • DMARDs, anti-TNF-α therapy, oral corticosteroids5,6 • Organ transplantation7,8 • Haematological malignancy9 CFTR, cystic fibrosis conductance regulator; CI, confidence interval; COPD, chronic obstructive pulmonary disease; DMARD, disease-modifying antirheumatic drug; NTM-LD, non-tuberculous mycobacterial lung disease; OR, odds ratio; TNF, tumor necrosis factor. 1. Szymanski EP, et al. Am J Respir Crit Care Med 2015; 192:618-28; 2. Kim RD, et al. Am J Respir Crit Care Med 2008; 178:1066-74; 3. Colombo RE, et al. Chest 2010; 137:629-34; 4. Andréjak C, et al. Thorax 2013; 68:256-62; 5. Winthrop KL, et al. Emerg Infect Dis 2009; 15:1556-61; 6. Brode SK, et al. Thorax 2015; 70:677-82; 7. Knoll BM, et al. Transpl Infect Dis 2012; 14:452-60; 8. Daley CL. Curr Opin Organ Transplant 2009; 14:619-24; 9. Chen CY, et al. Eur J Clin Microbiol Infect Dis 2012; 31:1059-66.

  20. The pattern of disease recognition has changed over time Changes in radiological appearance of NTM-LD cases in Queensland, Australia between 1999 and 2005 0.9 0.7 0.7 2.1 Shift from cavitary disease in middle-aged men who smoke to the nodular/bronchiectatic form of disease in older women NTM-LD, non-tuberculous mycobacterial lung disease. Thomson RM, et al. Emerg Infect Dis 2010; 16:1576-83.

  21. Bronchopulmonary factors associated with NTM-LD* Pneumo-coconiosis, Alveolar proteinosis Silicosis • COPD Cystic fibrosis Cystic fibrosis Bronchiectasis Previous TB infection *Please note size of shapes is not proportional to predicted level of association. COPD, chronic obstructive pulmonary disease; NTM-LD, non-tuberculous mycobacterial lung disease; TB, tuberculosis.Sexton P, Harrison AC. Eur Respir J 2008; 31:1322-33.

  22. Most common bronchopulmonary factors associated with NTM-LD • Bronchiectasis • COPD • Meta-analysis of 8 studies showed that the overall prevalence of NTM was 9.3% in patients with bronchiectasis1 • Most frequently NTM-LD‑associated condition in Germany3 • COPD treated with ICS therapyis a strong risk factor for NTM-LD4 • Cause and effect are hard to differentiate2 • No consistent evidence that NTM-LD and bronchiectasis severity are correlated2 • COPD and NTM-LD prevalence are both increasing4 Many patients with NTM-LD have at least one additional lung disease: either bronchiectasis, COPD or both5 COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease. 1. Chu H, et al. Arch Med Sci. 2014; 10:661-8; 2. Sexton P, Harrison AC. Eur Respir J 2008; 31:1322-33; 3. Ringshausen FC, et al. BMC Infect Dis 2013; 13:231; 4. Andréjak C, et al. Thorax 2013; 68:256-62, 5. Griffith DE, Aksamit TR. Clin Chest Med 2012; 33:283-95.

  23. Trends of associated diagnoses in hospitalized patients with NTM-LD between 2005 and 2011 Average annual percentage change of the rate of associated primary and secondary diagnoses per 1000 hospitalized patients with NTM-LD Mean annual % change (2005-2011) p-value p<0.05 Primary immunodeficiencies p<0.01 Human immunodeficiency virus p<0.001 Tuberculosis p<0.01 Alcohol-related disorders p<0.001 Influenza and pneumonia p<0.001 Chronic lower respiratory diseases p<0.001 COPD and emphysema While there has been a significant decline of immunodeficiencies and tuberculosis among NTM-LD-associated hospitalizations, other comorbidities such as cystic fibrosis and COPD are increasing p<0.05 Haemoptysis p<0.01 Bronchiectasis p<0.001 Primary hypertension p<0.01 Respiratory failure p<0.001 Disorders of water (…) balance p<0.01 Acute bronchitis and bronchiolitis p<0.001 Hypothyroidism p<0.001 Pleural effusion p<0.001 Cystic fibrosis –50 –40 –30 –20 –10 0 10 20 30 40 50 Declining trend Increasing trend Bars indicate 95% CI calculated from Poisson log-linear regression. CI, confidence interval; COPD, chronic obstructive pulmonary disease; NTM-LD, non-tuberculous mycobacterial lung disease. Adapted from Ringshausen FC, et al. BMC Infect Dis 2013; 13:231.

  24. NTMand disease

  25. NTM organisms commonly isolated from the respiratory tract • ~1/3 of identified species considered clinically significant2 • Growth rate classification (RGM vs. SGM) has clinically important repercussions:3 • RGM and SGM differ in their antimicrobial susceptibility and treatment regimens; RGM are more likely to be resistant • SGM mostly responsible for pulmonary and lymphonodal diseases • RGM can also affect cutis, bones and joints *In alphabetical order; †In northern Europe. MAC, Mycobacterium avium complex; NTM, non-tuberculous mycobacteria; RGM, Rapid-growing mycobacteria; SGM, Slow-growing mycobacteria. 1. Hoefsloot W, et al. Eur Respir J 2013; 42:1604-13; 175:367-416; 2. Tortoli E. FEMS Immunol Med Microbiol 2006; 48:159-78; 3. Tortoli E. Clin Microbiol Infect 2009; 15:906-10; 4. personal communication by scientific committee.

  26. Diagnosis and management of NTM-LD are challenging Guideline Late diagnosis Non-specific symptoms Symptoms may overlap with underlying lung disease1 Therapeutic challenge1–3 Multi-drug regimens Treatment for 1–2 years Risk of side effects Poor adherenceto evidence-based treatment guidelines4 Promotes antibiotic resistance Refractory disease Little data on efficacy of other drugs or interventions5 Cases should be referred to NTM-LD experts6 A multidisciplinary approach is required to adequately diagnose and manage patients with NTM-LD6,7 NTM-LD, non-tuberculous mycobacterial lung disease. 1. Griffith DE, et al. Am J Respir Crit Care Med 2007; 175:367-416; 2. Thomson RM, Yew WW. Respirology 2009; 14:12-26; 3. van Ingen J, et al. Drug Resist Updat 2012; 15:149-61; 4. Adjemian J, et al. Ann Am Thorac Soc 2014; 11:9-16; 5. Griffith DE, Aksamit TR. Curr Opin Infect Dis 2012; 25:218-27; 6. Haworth CS, et al. Thorax 2017; 72:ii1-ii64; 7. Ryu YJ, et al. Tuberc Respir Dis (Seoul) 2016; 79:74-84.

  27. Epidemiology

  28. Distribution of respiratory NTM isolates varies between geographical regions NTM isolates differ by country – these differences may have an impact on frequencies and manifestations of NTM-LD MAC M. kansasii M. xenopi M. malmoense RGM M. gordonae Other SGM MAC, Mycobacterium avium complex; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease; RGM, rapid-growing mycobacteria; SGM, slow-growing mycobacteria. Adapted from Hoefsloot W, et al. Eur Respir J 2013; 42:1604-13.

  29. Prevalence of NTM-LD is underestimated Estimated range of NTM-LD cases in the EU51,2 6000 5000 4000 Estimated number of patients with NTM-LD 3000 2000 1000 0 France Germany Italy Spain UK • Annual prevalence of NTM-LD is 3.3–6.2 per 100,000 in EU5 countries1,2 • Below threshold for orphan disease3 • Prevalence of NTM-LD has risen over the last 30 years, becoming more prevalent than tuberculosis4,5 NTM-LD, non-tuberculous mycobacterial lung disease. 1. Wagner D, et al. Poster (P1067) presented at: ERS International Meeting; September 6-10, 2014; Munich, Germany; 2. Ringshausen FC, et al. Emerg Infect Dis 2016; 22:1102-5; 3. Public summary of opinion on orphan designation: Amikacin sulfate for the treatment of nontuberculous mycobacterial lung disease. 2014. (Accessed February, 2018, at http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2014/05/ WC500166122.pdf.); 4. Marras TK, et al. Thorax 2007; 62:661-6; 5. Adjemian J, et al. Am J Respir Crit Care Med 2012; 186:553-8.

  30. Increasing diagnosis of NTM-LD Trends in annual prevalence of NTM-LD by sex and year in Germany* 3.5 MaleFemale Total 3.0 Rate/100,000 population 2.5 0 2009 2010 2011 2012 2013 2014 The estimated mean annual NTM-LD prevalence rate for Germany is 2.3 per 100,000 inhabitants in 2009 and increased to 3.3 in 2014 *Solid trend line indicates overall prevalence; dotted linear trend line, male prevalence; dashed linear trend line, female prevalence. NTM-LD, non-tuberculous mycobacterial lung disease. Ringshausen F.C. et al., Emerging Infectious Diseases: 2016, Vol. 22, No. 6.

  31. Why are the rates of NTM infections increasing? • Improved quality of diagnostic methods e.g. microbiological detection techniques1 Ageing population2,3 with an increase in the prevalence of COPD2 and other co-morbidities1 • Increased disease awareness1 • Tuberculosis infection can result in cross-protection against NTM4 NTM-LD infection rates may be underestimated5 Further research on the epidemiology of NTM infections by international research collaborations is required6 COPD, chronic obstructive pulmonary disease; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease.1. McShane PJ, Glassroth J. Chest 2015; DOI:10.1378/chest.15-0458; 2. van Ingen J, et al. Int J Tuberc Lung Dis 2010; 14:1176-80; 3. Al-Houqani M, et al. Chest 2012; 141:190-7; 4. Gopinath K, Singh S. PLoS Negl Trop Dis 2010; 4:e615; 5.van der Werf MJ, et al. BMC Infect Dis 2014; 14:62; 6. Ringshausen FC, et al. BMC Infect Dis 2013; 13: 231.

  32. Estimating NTM-LD numbers – an ongoing challenge • NTM is not reportable to public health authorities1 • NTM infections are reported in Queensland, Australia2 • Demographic changes (e.g. increased life expectancy)3 • Changing exposure conditions(e.g. popularity of showers)4 • Varying prevalence of disease-promoting factors (e.g. immunosuppression)5 • More than 172 NTM species described6 • Detection of NTM does not equate to a disease7 • NTM diagnostic methods used are variable between countries8 • Awareness of NTM varies between countries8 x The prevalence of NTM-LD is therefore likely to be underestimated7 NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease. 1. McShane PJ, Glassroth J. Chest 2015; DOI:10.1378/chest.15-0458; 2. Chou MP, et al. BMC Infect Dis 2014; 14:279; 3. Stout JE, et al. Int J Infect Dis 2016; 45:123-3 4. Thomson 2013 J Clin Microbiol 51 (9), 3006-11; 5. Henkle E, Winthrop K. Clin Chest Med 2015; 36:91-9; 6. Faria S, et al. J Pathog 2015; 2015:809014; 7. van der Werf MJ, et al. BMC Infect Dis 2014; 14:62; 8. personal communication by scientific committee.

  33. Impact of disease

  34. Quality of life is significantly reduced in patients with NTM-LD Health-related quality of life in 51 patients with NTM-LD from an ambulatory clinic in Canada (SF-36)† * * * Mean SF-36 scores * *p<0.001 General health perceptions Physical functioning Bodilypain Social functioning Most SF-36 scores were ≤ 10 points below the population-based norms, demonstrating that patients with NTM-LD have a reduction in their quality of life, associated with their lung function †Study period 08/2008-07/2009. NTM-LD, non-tuberculous mycobacterial lung disease; SF-36, medical outcomes short-form – 36 version 2. Mehta M, Marras TK. Respir Med 2011; 105:1718-25.

  35. NTM-LD can be a progressive, and ultimately lethal, lung disease • NTM-LD can become a progressive lung disease1,2 • If left untreated, MAC lung disease can result in extensive cavitary lung destruction and respiratory failure2 If left untreated, MAC lung disease can result in extensive cavitary lung destruction and respiratory failure2 Cystic fibrosis • Decline in lung function among patients with NTM-LD (n=68)*3 • Mean reduction in FEV1 was 48 mL/year • Normal range = 28.4-35.6 mL/year Impaired health-related quality of life in patients with NTM-LD is significantly associated with decline in lung function4 * Study from Taiwan (01/2000 – 04/2011). FEV1, forced expiratory volume in 1 sec; MAC, Mycobacterium avium complex; NTM-LD, non-tuberculous mycobacterial lung disease. 1. Weiss CH, Glassroth J. Expert Rev Respir Med 2012; 6:597-612; 2. Griffith DE, et al. Am J Respir Crit Care Med 2007; 175:367-416; 3. Lee MR, et al. PLoS One 2013; 8:e58214; 4. Mehta M, Marras TK. Respir Med 2011; 105:1718-25.

  36. Increasing hospitalization rate for NTM-LD Annual age-adjusted hospitalization rate for NTM-LD in Germany 1.5 1 Rate per 100,000 population Female Male 0.5 All 0 2005 2006 2007 2008 2009 2010 2011 Year From 2005 to 2011, the annual number of NTM-LD-associated hospitalizations in Germany increased by 4.9% on average (p<0.00001) NTM-LD, non-tuberculous mycobacterial lung disease.Adapted from Ringshausen FC, et al. BMC Infect Dis 2013; 13:231.

  37. Survival time correlates with the causative NTM species Rapid-growth mycobacteriaNon-rapid-growth mycobacteriaM. gordonaeM. avium complexM. malmoenseM. xenopi 100% 75% 50% Mortality distribution function 25% 0% 0 10 20 30 40 50 60 Retrospective study of 1282 Danish patients with pulmonary NTM isolates between 1997 and 20081 Other studies have confirmed M. xenopi infection results in increased mortality2 NTM, non-tuberculous mycobacteria. 1. Andréjak C, et al. Am J Respir Crit Care Med 2010; 181:514-21; 2. Gommans EP, et al. Respir Med 2015; 109:137-45.

  38. Mortality in high-risk patients with NTM-LD Retrospective study of patients with MAC lung disease between 1999 and 2005 in Japan 5-year all-cause mortality • Independent factors influencing 5-year mortality* • High Charlson comorbidity index in confirmed MAC patients and in patients with untreated chronic MAC • Presence of cavitary lesions in confirmed MAC patients as well as in treated MAC patients p=0.30 33.3 25.6 Mortality (%) 22.2 n=78 n=24 n=54 Mortality is associated with the presence of cavitary lesions Although statistical significance was not achieved, antimicrobial treatment (and sputum conversion after treatment) was associated with reduced mortality *Cox regression analysis after adjustment for clinical, microbiological and radiological confounders by univariate analysis. MAC, M. avium complex; NTM-LD, non-tuberculous mycobacterial lung disease. Ito Y, et al. Int J Tuberc Lung Dis 2012; 16:408-14.

  39. Mortality in high-risk patients with NTM-LD Mortality risk Yaeger, et al. 1973 BTS, et al. 2002 Griffith, et al. 2006 Jenkins, et al. 2008a Jenkins, et al. 2008b Andréjak, et al. 2010 Hayashi, et al. 2012 Ito, et al. 2012 Morimoto, et al. 2014 Gochi, et al. 2015 Gommans, et al. 2015 Kotilainen, et al. 2015 Moon, et al. 2016 Pooled estimate • Five-year overall mortality: 32% (95% CI 25–39%) • MAC-associated mortality 5–53% • Problem: large heterogeneity of the study populations • Negative predictors of mortality • Older age • Male gender • Fibrocavitary disease • Comorbidities • Macrolide resistance 0 10 20 30 40 50 60 70 80 90 100 Five-year mortality of patients with MAC lung disease (%) In most studies, the 5-year overall mortality rate was greater than 25% in patients with pulmonary MAC disease CI, confidence interval; MAC, Mycobacterium avium complex; NTM, non-tuberculous mycobacteria; NTM-LD, non-tuberculous mycobacterial lung disease. v.d. Laan R, Obradovic M, Poster DGP-Kongress 2017, Stuttgart, Deutschland.

  40. Higher mortality with cavitary disease MAC-specific mortalityaccording to radiographic features Total (n=634) 100% • Multivariate analysis of risk factors* Hazard Ratio [95% confidence interval] • FC (± NB): 5.3 [2.634-10.763], p<0.001 • BMI < 18.5 kg/m2: 4.3 [1.655-11.270], p=0.003 Nodular/bronchiectatic (NB) (n=482) Fibrocavitary (FC) or fibrocavitary + nodular/bronchiectatic (n=135) 80% Other (n=17) 60% Estimated Mortality (%) 40% p<0.001 20% ns 0% 0 2 4 6 8 10 12 Year Fibrocavitary disease or fibrocavitary + nodular/bronchiectatic disease and low body mass index were associated with greater mortality *Multivariate Cox proportional hazard model. BMI, body mass index; FC, fibrocavitary; MAC, Mycobacterium avium complex; NB, nodular/bronchiectatic; NTM-LD, non-tuberculous mycobacterial lung disease; ns, not significant.Adapted from Hayashi M, et al. Am J Respir Crit Care Med 2012; 185:575-83.

  41. Summary • NTM are related to M. tuberculosis,1however are not obligate pathogens and can survive in the environment, including water distribution systems2 • NTM can be classified based on their growth rate1 • The mycobacterial outer membrane supports dissemination and adherence, helping to form biofilms2 • Different species of NTM have different clinical relevance3,4 • Pulmonary disease is the most common form of NTM disease, with both nodular/bronchiectatic and fibrocavitary forms being observed5 • Risk factors for development of NTM include geographic location,6 genetic factors7–9 and underlying lung conditions1,10 • NTM diagnosis has become more frequent – this may be due to increased awareness10,11 • Disease prevalence between countries is also variable12 • NTM is a progressive lung disease13, impacting patient quality of life14 • Patients with fibrocavitary disease are at higher risk of mortality than those with nodular/bronchiectatic disease15 NTM, non-tuberculous mycobacteria. 1. Fedrizzi T, et al. Sci Rep 2017; 7:45258; 2. Falkinham JO, 3rd. J Appl Microbiol 2009; 107:356-67; 3. van Ingen J, et al. Thorax 2009; 64:502-6; 4. Schönfeld N, et al. Pneumologie 2013; 67:605-33; 5. Griffith DE, et al. Am J Respir Crit Care Med 2007; 6. Adjemian J, et al. Am J Respir Crit Care Med 2012; 186:553-8; 7. Szymanski EP, et al. Am J Respir Crit Care Med 2015; 192:618-28; 8. Kim RD, et al. Am J Respir Crit Care Med 2008; 178:1066-74; 9. Colombo RE, et al. Chest 2010; 137:629-34; 10. Johnson MM, Odell JA. J Thorac Dis 2014; 6:210-2; 11. Thomson RM, et al. Emerg Infect Dis 2010; 16:1576-83; 12. Hoefsloot W, et al. Eur Respir J 2013; 42:1604-13; 13. Weiss CH, Glassroth J. Expert Rev Respir Med 2012; 6:597-612; 14. Mehta M, Marras TK. Respir Med 2011; 105:1718-25; 15. Hayashi M, et al. Am J Respir Crit Care Med 2012; 185:575-83.

  42. Glossary Alveolar proteinosis Rare lung disease characterised by abnormal accumulation of surfactant lipoprotein in the alveoli of the lungs BiofilmA group of microorganisms that are stuck together and adhere to a surface comprised of extracellular polymeric substances Charlson comorbidity indexSystem with 19 categories used to predict 10-year mortality EU5 countriesFrance, Germany, Italy, Spain, United Kingdom Lady Windermere syndromeNodular/bronchiectatic form of NTM‑LD, particularly associated with tall, thin postmenopausal women Orphan disease Life-threatening or chronically debilitating disease affecting at a maximum of 5 in 10,000 people in the EU, where marketing of medicines to treat the disease (potential orphan drugs) would be unlikely to justify investment needed for its development PneumoconiosisDisease of the lungs caused by inhalation of dust SilicosisDisease of the lungs caused by inhalation of crystalline silica dust NTM-LD, non-tuberculous mycobacterial lung disease.

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