Epidemiology of NTM Lung Disease

Transcription

1 Epidemiology of NTM Lung Disease NTM Lecture Series for Providers National Jewish Health Denver, CO October 19-20, 2017 Ted Marras, MD FRCPC MSc Toronto Western Hospital / University Health Network

2 Disclosures Site investigator Insmed Consultant Insmed, RedHill, Horizon CME Astra Zeneca

3 Epidemiology NTM - Objectives Disease frequency Questions and challenges Geographic variation Period prevalence estimating population burden Common risk factors Temporal trends Financial burden Mortality

4 Epidemiology NTM Study Design What do we want to measure? All patients with disease Microbiology Clinical + Radiological = Disease How do we measure it? Population-based Longitudinal data - Questions and Challenges Not reportable

5 NTM a Reportable Disease? Non-pulmonary Study Design Isolation usually disease Reportability likely feasible, beneficial Pulmonary Disease in ~50% with MAC isolate ~90% with >1 sputum + Detailed data collection (micro + clinical + radiology) required Oregon (Winthrop, Annals ATS 2017) Period of detailed reportability, ongoing lab-based Queensland, Australia (Thomson, Annals ATS 2017) History of detailed reporting evolved to ongoing lab-based Known association between isolation and disease permits inferences on disease rates and trends Regional clusters may help understand pathophysiology

6 Annual Rates of NTM -North America, population based Region USA Medicare (>65 y) (Adjemian AJRCCM 2012) Ontario, Canada, province-wide, (Marras, EID 2013) Four US HMO / IHCDSs, (Prevots AJRCCM 2010) Oregon, state-wide, (Cassidy, CID 2009) Hawaii, single large HMO, (Adjemian EID 2017) Median (range) Disease (annual frequency)* ~ 47 (elders) ~ (5.5-18) * Annualized, per 100,000 population / year; overall average or final year of study (generally excludes M. gordonae)

7 Annual Rates of NTM -Global, population based Region Disease (annual frequency)* Brazil (3 studies, ) British Isles (5 studies, ) Continental Europe (8 studies, ) Australia (3 studies, ) North America - median (range) 5.6 ( ) * Annualized, per 100,000 population / year; overall average or final year of study ( Generally excludes M. gordonae)

8 Emerging NTM epidemiology - North America disease by species Study N Most Common Species New York City, single institution, (Bodle, EID 2008) Oregon, state-wide, (Henkle, Ann ATS 2015) Four US HMO / IHCDSs, (Prevots AJRCCM 2010) Charlottesville VA, single institution, (Satyanarayana, BMC ID 2011) Hawaii, state-wide, , single HMO (Adjemian EID 2017) Ontario, province-wide, 2010 (Marras, EID 2013) 81 1,146 1, ,294 MAC M. avium complex RGM rapidly growing mycobacteria MAC (80%) MAC (86%) MAC (80%) MAC (69%) RGM (9%) abscessus /chelonae (7%) abscessus /chelonae (12%) kansasii (5%) MAC (67%) MAC (64%) abscessus (18%) xenopi (23%) xenopi (6%) kansasii (1.2%) fortuitum (6%) xenopi (5%) fortuium (16%) abscessus (3%) kansasii (5%) fortuitum (<1%) kansasii (6%) abscessus (4%) fortuitum (3%)

9 Emerging NTM epidemiology - North America disease by species Study N Most Common Species New York City, single institution, (Bodle, EID 2008) Oregon, state-wide, (Henkle, Ann ATS 2015) Four US HMO / IHCDSs, (Prevots AJRCCM 2010) Charlottesville VA, single institution, (Satyanarayana, BMC ID 2011) Hawaii, state-wide, , single HMO (Adjemian EID 2017) Ontario, province-wide, 2010 (Marras, EID 2013) 81 1,146 1, ,294 MAC M. avium complex RGM rapidly growing mycobacteria MAC (80%) MAC (86%) MAC (80%) MAC (69%) RGM (9%) abscessus /chelonae (7%) abscessus /chelonae (12%) kansasii (5%) MAC (67%) MAC (64%) abscessus (18%) xenopi (23%) xenopi (6%) kansasii (1.2%) fortuitum (6%) xenopi (5%) fortuium (16%) abscessus (3%) kansasii (5%) fortuitum (<1%) kansasii (6%) abscessus (4%) fortuitum (3%)

10 Emerging NTM epidemiology - North America disease by species Study N Most Common Species New York City, single institution, (Bodle, EID 2008) Oregon, state-wide, (Henkle, Ann ATS 2015) Four US HMO / IHCDSs, (Prevots AJRCCM 2010) Charlottesville VA, single institution, (Satyanarayana, BMC ID 2011) Hawaii, state-wide, , single HMO (Adjemian EID 2017) Ontario, province-wide, 2010 (Marras, EID 2013) 81 1,146 1, ,294 MAC M. avium complex RGM rapidly growing mycobacteria MAC (80%) MAC (86%) MAC (80%) MAC (69%) RGM (9%) abscessus /chelonae (7%) abscessus /chelonae (12%) kansasii (5%) MAC (67%) MAC (64%) abscessus (18%) xenopi (23%) xenopi (6%) kansasii (1.2%) fortuitum (6%) xenopi (5%) fortuium (16%) abscessus (3%) kansasii (5%) fortuitum (<1%) kansasii (6%) abscessus (4%) fortuitum (3%)

11 Emerging NTM epidemiology - North America disease by species Study N Most Common Species New York City, single institution, (Bodle, EID 2008) Oregon, state-wide, (Henkle, Ann ATS 2015) Four US HMO / IHCDSs, (Prevots AJRCCM 2010) Charlottesville VA, single institution, (Satyanarayana, BMC ID 2011) Hawaii, state-wide, , single HMO (Adjemian EID 2017) Ontario, province-wide, 2010 (Marras, EID 2013) 81 1,146 1, ,294 MAC M. avium complex RGM rapidly growing mycobacteria MAC (80%) MAC (86%) MAC (80%) MAC (69%) RGM (9%) abscessus /chelonae (7%) abscessus /chelonae (12%) kansasii (5%) MAC (67%) MAC (64%) abscessus (18%) xenopi (23%) xenopi (6%) kansasii (1.2%) fortuitum (6%) xenopi (5%) fortuium (16%) abscessus (3%) kansasii (5%) fortuitum (<1%) kansasii (6%) abscessus (4%) fortuitum (3%)

12 Epidemiology NTM - Species frequency by region MAC / M. kansasii M. abscessus MAC M. abscessus M. simiae MAC M. kansasii ~ malmoense M. xenopi MAC M. abscessus M. kansasii ~ fortuitum MAC M. abscessus / xenopi / kansasii MAC M. kansasii M. abscessus

13 NTM species - pathogenic potential

14 Pr N op ot e fo rty rr o ep f p ro res du e ct nte io r n Population Burden

15 NTM epidemiology - population burden Study Design Chronic disease Minority treated 18% (Prevots, AJRCCM 2010) Treatment success 56% (Field, Chest 2004) Recurrence (<4 years) 48% (Wallace, Chest 2014) Median survival 10 years

16 NTM epidemiology Study Design Chronic disease Minority treated 18% (Prevots, AJRCCM 2010) Treatment success 56% (Field, Chest 2004) Recurrence (<4 years) 48% (Wallace, Chest 2014) Median survival 10 years Ongoing NTM isolation often absent Small burden of organisms Practice patterns - population burden

17 Measuring population burden - Real world limitations Study Design Incidence - number of new cases of a condition arising during a specific period of time

18 Measuring population burden Incidence - Real world limitations Study Design All pts with micro criteria this year

19 Measuring population burden Incidence - Real world limitations Study Design Look back period of adequate duration (REMOVE prevalent cases) All pts with micro criteria this year

20 Measuring population burden Incidence - Real world limitations Study Design Look back period of adequate duration (REMOVE prevalent cases) All pts with micro criteria this year Prevalence - number of cases in the population at a given time, divided by the number of individuals in the population

21 Measuring population burden Incidence - Real world limitations Study Design Look back period of adequate duration (REMOVE prevalent cases) All pts with micro criteria this year Prevalence All pts with micro criteria this year

22 Measuring population burden Incidence Prevalence - Real world limitations Study Design Look back period of adequate duration (REMOVE prevalent cases) All pts with micro criteria this year Look back of adequate duration (INCLUDE previously diagnosed but still ongoing cases) All pts with micro criteria this year

23 Measuring population burden Study Design - metrics Incidence Number of new cases of a condition arising during a specific period of time, divided by the number of individuals in the population Prevalence Number of cases in the population at a given time, divided by the number of individuals in the population Period Prevalence Proportion of a population that has the condition at some time during a given period Includes people who already have the condition at the start of the study period and those who acquire it during that period

24 NTM population burden Study Winthrop, AJRCCM 2010 (Oregon, ) Prevots, AJRCCM 2010 (4 US IHCDS, 94-06) Adjemian, AJRCCM 2012 (US Medicare 97-07) Adjemian, Ann ATS 2017 (Hawaii ) Marras, EID 2013 (Ontario, ) Methods Comprehensive Portland tri-county Clinical record review Four US IHCDS ATS micro definition with some validation Representative 5% Medicare sample (>65yr) ICD9 search Single large HMO ATS micro definition Province-wide Micro diagnosis - Period prevalence Period Prevalence / Cumulative Incidence 2-year PP All ages = 8.6/100,000 >50 yrs = 20.4/100,000 3-year CI <60 yr ~ 4/100, yr ~ 40/100, yr ~ 100/100,000 >80 yr ~ 220/100,000 <11-year PP >65 yrs = 112/100,000 9 year PP >65 yrs ~350/100, yrs ~100/100,000 5-year PP All ages = 41.3/100,000

25 Risk Factors

26 Susceptible host paradigm NTM Widespread / ubiquitous exposure Disease uncommon (approx 40/100,000)

27 NTM PD risk factors Study Design - age Region (N studies) Overall (weighted) Mean age Range North America (N=6) Europe (N=12) Prevots, Clin Chest Med, 2015

28 NTM PD risk factors - age in Ontario Al-Houqani, Chest 2012

29 NTM PD risk factors Study Design - sex

30 NTM PD risk factors - sex May vary by disease type, based on presence of pre-existing structural lung disease Absent ~ 85% women Present varies by population

31 Sex distribution NTM PD - Ontario, Canada Ontario population (incident NTM-PD) Species (N) Female All (9,681) 51% MAC (6,431) 53% M. xenopi (2,310) 45% M. abscessus (255) 61% M. kansasii (162) 33% NTM clinic All (771) 65%

32 Host factors in Pulmonary NTM - Structure vs Function Pre-existing structural lung disease Emphysema Bronchiectasis* Fibrosis

33 Host factors in Pulmonary NTM - Structure vs Function Pre-existing structural lung disease Emphysema Bronchiectasis* Fibrosis Functional defect - covert impairment of mucociliary defense CFTR mutations Ciliary impairment Immune dysregulation etc.

34 Secondary NTM PD - Structural lung disease COPD Risk factor in 30-40% of NTM-PD patients Population-based study in Denmark: 332 NTM patients 3,320 population controls OR of COPD in NTM patients = 15.7 Andrejak, Thorax 2013

35 NTM-PD with OLD in Ontario Methods Cohort Exposure - COPD and / or asthma Validated claims definitions Outcome - NTM PD ATS microbiologic definition, excluding Analysis Previously positive for same species M. gordonae Incidence per 100,000 person-years HRs Comparing OLD and non-old Adjusted for age, sex, and predisposing conditions (bronchiectasis, CKD, DM, GERD, HIV, HSCT, lung cancer, RA, SOT, TB) Marras et al. ERJ 2016

36 NTM-PD with OLD in Ontario Results Total 6,290,603 adult Ontarians (>35 yrs) NTM Pulmonary Disease No OLD N=5,436,773 COPD N=543,119 Asthma N=406,712 Number cases 4,398 4,538 1,850 Incidence* (95% CI) ( ) ( ) Fully-adjusted HR** (95% CI) 1.0 (reference) 8.7 ( ) * Incidence per 100,000 person-years (Poisson 95% confidence intervals) ** Adjusted for age, sex, bronchiectasis, CKD, DM, GERD, HIV, HSCT, lung cancer, RA, SOT, TB 52.8 ( ) 5.1 ( ) Marras et al. ERJ 2016

37 Secondary NTM PD Inhaled Corticosteroids + Obstructive Lung Disease Population-based study in Denmark: 112 NTM patients compared with 1,120 controls ORs among NTM patients for: Without ICS - ICS + OLD Current ICS COPD 7.6 ( ) 29.1 ( ) Asthma 4.3 ( ) 1.5 ( ) Andrejak, Thorax 2013

38 NTM with ICS in OLD, Ontario, Canada Methods - Nested case control Cohort: Ontarians 66 yrs with actively treated asthma, COPD or ACOS Cases incident NTM-PD defined microbiologically Controls (4:1) matched by age, sex, cohort entry year, duration and type of OLD Exposure ICS use (current, prior, none) Analyses - ORs Exposure to ICS - cases vs controls Adjusted for demographics, comorbidities, immunesuppressive meds, OLD severity ICS inhaled corticosteroids Brode et al. ERJ 2017

39 NTM with ICS in OLD, Ontario, Canada Results 417,494 seniors with treated OLD (2,966 cases incident NTM-PD) Asthma = 83,056 / ACOS = 68,383 / COPD = 266,055 Primary analysis - All patients with OLD Exposure No ICS Prior ICS Current ICS NTM Cases N= % (592) 15.8% (469) 64.4% (1908) * All results fully adjusted Brode et al. ERJ 2017 Controls N=11, % (4175) 22.3% (2647) 43.1% (5107) Adjusted OR (95% CI) 1.0 (ref) 0.94 ( ) 1.86 ( ) P value <0.001 Secondary analyses (current ICS) COPD 1.96 ( ) p<0.001 ACOS 1.74 ( ) p=0.002 Asthma 1.56 ( ) p=0.18

40 NTM PD risk factors - Immune dysregulation (RA) Study Design Risk Factor Crude OR Fully adjusted OR Rheumatoid arthritis* 4.7 ( ) 1.9 ( ) Anti-TNFa** 2.4 (1.3, 4.4) 2.2 (1.1, 4.4) Leflunomide** 3.5 (1.3, 9.6) 3.7 (1.0, 13.3) Sulfasalazine** 1.9 (0.6, 6.2) 2.8 (0.6,12.6 ) High-risk DMARD** 5.8 (1.5, 23.4) 23.9 (3.0,192.4) * Population-based cohort study, compared RA vs non RA patients ** Population-based RA study - among RA patients High-risk DMARD: Cyclophosphamide, Azathioprine, Cyclosporine, Mycophenolate, Chlorambucil Brode, Chest 2014 & Thorax 2015

41 Temporal Trends

42 Temporal trends Study Design Brode et al, IJTLD studies reporting trends of rates of NTM disease ( ) in Canada, USA, Europe, Japan, Australia Temporal Rates by region Climbing 75% Stable % Declining 12.5% - Systematic review

43 NTM disease incidence over time with fitted regression lines Median slope = (median annual increase in NTM cases per 100,000) Brode et al, IJTLD 2014

44 Most recent temporal disease trends - North America Study Prevots AJRCCM 2010 (4 US IHCDS, ) - Micro + ICD9 Alhouqani, Chest 2012 (Ontario, Canada, ) - ATS micro criteria Adjemian, AJRCCM 2012 (US Medicare 97-07) - ICD9 Henkle, AnnATS 2015 (Oregon, state-wide, ) - ATS micro criteria Adjemian, Ann ATS 2017 (Hawaii state-wide, single HMO, ) - ATS micro criteria Temporal trends % / year (prevalence) 10% / year (MAC prevalence) 8.5% / year (prevalence) 2.2% / year (incidence) 9.6% / year (prevalence)

45 Most recent temporal trends Region Europe / British Isles Japan Observations Publications studies small-large increases 2 studies fluctuating Publications 2014, studies Increasing

46 Temporal trends - ON species Five year period prevalence NTM-PD by species (Ontario, Canada) Increases mostly driven by MAC

47 Fictitious? Looking harder, seeing more

48 Fictitious NTM increase? Looking harder, seeing more? Ontario Stable number specimens submitted (fluctuating 37k - 41k) 30% increase in number of NTM isolates Annual prevalence of MAC PD /100,000 Al-Houqani, CRJ 2011, Chest 2012

49 Fictitious? Looking harder, seeing more Host factors? Less mycobacterial immunity - TB, BCG Age, HIV, cancer, destroyed lung

50 Host factors increasing NTM? Age, HIV, cancer, destroyed lung Modeled effects of ageing, COPD, immune suppression (HIV, SOT, anti-tnfa) in Ontario on annual prevalence of MAC PD Observed increase: /100,000 = 2.46 Expected increase: Ageing = 0.57 COPD = 0.09 Immune = 0.60 Total = 1.26 Unexplained increase: = 1.20 Al-Houqani, Chest 2012

51 Fictitious? Looking harder, seeing more Host factors? Less mycobacterial immunity - TB, BCG Age, HIV, cancer, destroyed lung Pathogen factors? Difficult to discern

52 Fictitious? Looking harder, seeing more Host factors? Less mycobacterial immunity - TB, BCG Age, HIV, cancer, destroyed lung Pathogen factors? Difficult to discern Host-pathogen interactions? Increased inoculation Tub bathing showering More household / recreational water devices Changes in water treatment and distribution

53 Financial Costs NTM-PD

54 Financial Costs Study Design Ballarino et al., Resp Med 2009 Antibiotic costs, 27 patients (NIH natural history study) 89% MAC, 21% M. abscessus Treatment - median (range) Number of drugs 5 (1-10) Duration 2638 ( ) drug-days Cost $19,876 ($398-70,917) Subjects with high costs higher adjusted likelihood M. abscessus OR=9.5 (95% CI ) Extensive disease OR=4.2 (95% CI 0.6e59.3) - Patient level drug costs

55 Financial Costs Study Design Leber et al., ERJ 2011 Total health care costs, 91 treated NTM-PD patients, Toronto clinic Treatment median (quartiles) Duration = 14 (9-23) months Total cost (CAD) = $ 4,916 (2,934-9,063) Monthly drug costs (CAD) All patients - $ 321 ( ) Exclusively oral therapy $ 289 ( ) Included IV therapy $ 1,161 (795-1,646) High treatment costs associated with M. abscessus, M. xenopi IV therapy - Patient level care costs

56 Financial Costs - Patient level care costs Study Design Leber et al., ERJ 2011 Projected costs of guideline-recommended, 18 months course of oral therapy (2008 costs) Regimen Total cost (CAD) Total cost (USD) Drug Non-drug Total Drug Non-drug Total Daily (Azi) 3,818 2,011 5,829 8,942 2,703 11,645 Daily (Clari) 4,990 2,011 7,001 9,623 2,703 12,326 TIW (Azi) 2,742 2,011 4,753 6,479 2,703 9,182 TIW (clari) 2,602 2,011 4,613 4,954 2,703 7,657

57 Financial Costs Study Design Naumova et al, J Pub Health Policy 2016 Hospitalizations for infections with opportunistic premise plumbing pathogens (OPPP) Medicare and Medicaid NTM 35,080 hospitalizations Charges per case 27.5 k Payments per case 9.6 k - Hospitalizations

58 Financial Costs Study Design Strollo et al, Ann ATS 2015 Estimated US annual cases NTMPD, direct medical costs Cost estimates applied to prevalence from Medicare beneficiary data ( ), adjusted for under-coding and to include persons <65 yrs old 2010 estimated 86,244 cases Total costs - $815 million 87% inpatient related ($709 million) 13% were outpatient related ($106 million) 76% mdication costs projected (for pop n + 8% annual case increase) 181,037 national annual cases ($1.7 billion) - US national estimates

59 Financial Costs Study Design Collier et al, Epidemiol Infect 2012 Private, Medicaid, Medicare data Lacked detailed data for NTM, but Outpatient cases N=1,455 Hospitalized cases N=366 Still surprisingly high proportion of hospitalized cases? - Payer care costs

60 Financial Costs Study Design Diel al, ERS 2017 Large sample of German population health insurance 125 incident cases of NTM=PD in , each matched to 10 controls (age, sex, CCI category*) Mean direct expenditure (39 months / death) NTM-PD patient 39, Matched control payer costs - Germany Hospitalizations three times higher in NTM-PD group; accounted for 63% of total costs Attributable annual direct costs and indirect work-loss costs in NTM-PD patients were and per control patient, respectively. * Charlson Comorbidity Index stratifies by mortality risk, generated from patients surviving acute care hospitalization (1980s)

61 Survival / Mortality

62 Survival / Mortality NTM-PD -different studies Population Mortality Among the entire population how many people die from NTM-PD? Survival in NTM-PD Among patients with NTM-PD, what is the survival?

63 Population Mortality NTM-PD - Death certificate studies Morimoto, et al. Ann ATS 2014 (Japan) Crude NTMosis-related mortality rates increased /100, /100, /100,000 Age-adjusted rates also increased Vinnard, et al. Ann ATS 2015 (USA) National death certificate data Rates of NTM-related deaths increasing

64 Survival of Patients with NTM-PD - Single program / clinic Hayashi (Saitama / Tokyo, AJRCCM 2012) 634 MAC patients, mean age 65 yrs 5-yr mortality 23% Ito (Kyoto, IJTLD 2012) 164 MAC patients, mean age 69 yrs 5-yr mortality 24% (treated 22%, untreated chronic 33%) Kotilainen (Helsinki, ScandJID 2013) 61 NTM patients (61% MAC), mean age 63 yrs 5-yr mortality 30% Fleshner (Bethesda, IJTLD 2016) 106 NTM patient (61% MAC), median age 55 yrs 5-yr mortality 18%

65 Survival of Patients with NTM-PD - Pop n / quasi-pop n based Andrejak (Denmark, AJRCCM 2010) 335 definite, 238 possible disease, mean age 62 yrs MAC 41-57% M. xenopi 5-8% M. malmoense 3-8% M. abscessus 3-7% 5-yr mortality 40-45% (highest with M. xenopi) Adjemian (Medicare sampling, AJRCCM 2012) Age >65 yrs, non-hmo enrolled, ICD9 Odds ratio for mortality (vs non-ntm) = 1.4 ( )

66 Survival of Patients with NTM-PD - Pop n / quasi-pop n based Diel (Germany, ERS 2017) Large sample of German population health insurance 125 incident cases of NTM=PD in Matched each case to 10 controls by age, sex, and CCI category* Mortality over 39 months 22.4% vs 6.0% (p<0.001) HR 3.64 ( ) * Charlson Comorbidity Index stratifies by mortality risk, generated from patients surviving acute care hospitalization (1980s)

67 Survival of Patients with Pulmonary NTM Methods Population-based, matched cohort study Incident ( ): NTM disease (NTM-PD - ATS micro criteria) Isolation only (NTM-PI - single isolate) Matched to unexposed population-based controls by age, sex, index date, propensity score: Twelve propensity scores one for each species-condition (e.g. MAC-PD, MAC-PI, xenopi-pd, xenopi-pi ) Each estimating patient-level likelihood of a species-condition - Ontario Marras et al, EID 2017

68 Survival of Patients with Pulmonary NTM Results 20,617 people had pntm isolations ( ) 10,936 (53%) NTM-PI 9,681 (47%) NTM-PD NTM-PD (N = 9,681) 51% females Age - median (quartiles) - 70 (58-78) yrs Asthma in 35%, COPD in 51% (validated definitions) Species groups MAC 65% (6,323) M. xenopi 23% (2,263) M. abscessus 2.5% (245) - Ontario Marras et al, EID 2017

69 1 Cumulative survival of NTM isolation by species 0.9 Survival M. abscessus M. fortuitum MAC M. xenopi M. kansasii N=447, median age 62 yrs N=996, median age 64 yrs N=12,219, median age 68 yrs N=5,277, median age 68 yrs N=274, median age 66 yrs Survival Survival time (years) (years) Marras et al, EID 2017

70 Survival of Patients with NTM-PD Variable Value (N=9,681) Adjusted HR - Results 95% CI P-value NTM species MAC (reference) 6,323 (65.3%) M. xenopi 2,263 (23.4%) 1.22 ( ) <.0001 M. fortuitum 265 (2.7%) 1.02 ( ) M. abscessus 245 (2.5%) 0.98 ( ) M. kansasii 158 (1.6%) 1.25 ( ) All other species 427 (4.4%) 0.94 ( ) Marras et al, EID 2017

71 Survival of Patients with NTM-PD (matched) - Ontario Group Total 1-year Survival 5-year Survival Hazard ratio (95% CI) NTM % 65.6% 1.63 ( ) Control % 78.7% (ref) MAC % 66.7% 1.57 ( ) Control % 78.5% (ref) M. xenopi % 59.9% 1.84 ( ) Control % 77.7% (ref) M. fortuitum % 69.7% 1.25 ( ) Control % 80.7% (ref) M. abscessus % 79.2% 1.49 ( ) Control % 87.3% (ref) M. kansasii % 63.5% 2.53 ( ) Control % 83.0% (ref) Marras et al, EID 2017

72 Survival of Patients with NTM-PI (matched) Group Total 1-year Survival 5-year Survival - Ontario Hazard ratio (95% CI) NTM % 76.1% 1.33 ( ) Control % 82.6% (ref) MAC % 75.9% 1.33 ( ) Control % 82.3% (ref) M. xenopi % 74.5% 1.32 ( ) Control % 81.5% (ref) M. fortuitum % 78.8% 1.47 ( ) Control % 86.4% (ref) M. abscessus % 82.2% 1.39 ( ) Control % 85.7% (ref) M. kansasii % 55.3% 2.02 ( ) Control % 85.3% (ref) Marras et al, EID 2017

73 Survival with any NTM isolation (matched) Group Total 1-year Survival 5-year Survival - Ontario Hazard ratio (95% CI) NTM % 71.3% 1.47 ( ) Control % 80.8% (ref) MAC % 71.2% 1.45 ( ) Control % 80.4% (ref) M. xenopi % 68.3% 1.54 ( ) Control % 79.9% (ref) M. fortuitum % 76.4% 1.39 ( ) Control % 84.9% (ref) M. abscessus % 80.5% 1.45 ( ) Control % 86.6% (ref) M. kansasii % 60.2% 2.29 ( ) Control % 84.0% (ref) Marras et al, EID 2017

74 Survival Patients with NTM-PD vs NTM-PI - Ontario Species Group Total 1-year 5-year Adjusted HR Survival Survival (95% CI) All Disease % 63.1% 1.23 ( ) Isolation % 73.4% (ref) MAC Disease % 64.7% 1.16 ( ) Isolation % 73.2% (ref) M. xenopi Disease % 56.8% 1.39 ( ) Isolation % 71.9% (ref) M. fortuitum Disease % 64.8% 1.17 ( ) Isolation % 76.0% (ref) M. abscessus Disease % 72.8% 1.14 ( ) Isolation % 77.1% (ref) M. kansasii Disease % 62.3% 1.15 ( ) Isolation % 52.0% (ref) Marras et al, EID 2017

75 Multi-species vs single-species NTM-PD - survival, Ontario Patients with multi-species NTM-PD: Any combination (n=620) had greater mortality than single-species NTM-PD (any species, n=9,061) HR=1.19 ( ) MAC plus M. xenopi (n=354) had greater mortality than either species alone (n=8,059) HR=1.23 ( ) Marras et al, EID 2017

76 Survival of Patients with Pulmonary NTM Conclusions Compared with extensively matched unexposed controls from the general population, patients with NTM- PD, NTM-PI, and any NTM isolation have higher mortality Patients with MAC or M. xenopi NTM-PD have higher mortality than patients with NTM-PI M. xenopi-pd has higher mortality than MAC-PD Repeatedly positive cultures for >1 NTM species is associated with greater mortality - Ontario Marras et al, EID 2017

77 Epidemiology NTM Disease frequency Questions and challenges Geographic variation Period prevalence Common risk factors Temporal trends Financial burden Mortality - Summary

78 Thank you Ontario Thoracic Society PSI Foundation Mohammed Alhouqani Sarah Brode Michael Campitelli Pamela Chedore Hannah Chung Andrea Gershon Frances Jamieson Jeff Kwong Hong Lu Alex Marchand-Austin David Mendelson Kevin Winthrop Alicia Ying

79 Incident Pulmonary NTM Disease in Ontario, Canada, (%) MAC M. xenopi M. fortuitum M. abscessus M. kansasii M. chelonae Other

80 Risk of NTM with Inhaled Steroids in OLD Dose-response One-year cumulative ICS dose L o w d o s e IC S M o d e r a te d o s e IC S H ig h d o s e IC S Treated NTM disease Current ICS use OR = 1.65 ( ) Specific ICS (current use) Fluticasone: 2.09 ( ) Budesonide: 1.19 ( ) O d d s r a tio fo r N T M d is e a s e * All results fully adjusted Brode et al. ATS meeting 2016

81 Annual prevalence of pulmonary NTM isolation Ontario Per 100,000 NTM - Annual isolation prevalence NTM - Annual disease prevalence TB - Annual incidence Marras et al. Emerg Infect Dis (11).