we conducted a population - based matched cohort study using linked health administrative data and mycobacteriology as described previously ( 13 ) , including all ontario residents with incident pulmonary ntm isolation diagnosed during 20012013 , and unexposed controls matched by age , sex , index date , and propensity score ( 14 ) . additional details about the data sources and methods are provided in the technical appendix . using microbiological criteria from current guidelines ( 5 ) , we defined 2 mutually exclusive groups . one positive sputum sample defined ntm - pi , whereas > 1 positive sputum sample for the same species or 1 positive bronchoscopic or biopsy specimen defined ntm - pd . we disregarded mycobacterium gordonae isolates and excluded persons with prior ( 19982000 ) ntm isolation . we calculated 12 propensity scores ( estimating the patient - level likelihood of species  condition combinations ) , 1 for each species  condition combination of interest , comprising the species groups m. avium complex ( mac ) , m. xenopi , m. fortuitum , m. abscessus , m. kansasii , and other , according to the condition - states ntm - pi and ntm - pd . we sought to match each patient with ntm ( exposed person ) to an ontario resident without ntm ( unexposed control ) who shared the age ( years ) , sex , and index date (  90 days ) , and had a propensity score value within 0.2  sd of the exposed patient ( 15 ) . index date was date of first positive culture for exposed patients and was randomly assigned to potential unexposed controls by using a random number generator . primary analyses compared survival of propensity score  matched exposed with unexposed persons , for each species  condition group ( e.g. , patients with mac ntm - pd vs. their population - matched unexposed controls ) . we also compared , for individual ntm species - groups and all species - groups combined , survival of patients with any isolation ( ntm - pi or ntm - pd ) to their propensity score  matched controls and survival of all patients with ntm - pd or ntm - pi ( without matching ) . we also calculated standardized mortality ratios , using age- ( in 5-year strata ) and sex - specific all - cause death rates in the ontario general population during the study period ( 20012013 ) , as an intuitive mortality risk assessment without full adjustment . to study whether ntm - pd with > 1 ntm species ( multispecies ntm - pd ) affected survival , we compared the survival of ntm - pd patients infected with 1 species with survival of patients who fulfilled criteria for > 1 species . finally , we examined associations between demographic and clinical factors with death . follow - up began on the index date and ended at death or end of the study period , whichever came first . survival analyses comprised cox proportional hazards models . including low - frequency covariates ( table 1 ) in propensity score calculation led to substantially fewer ntm patients successfully matching to an unexposed person . these covariates were explored for inclusion by using a hosmer - lemeshow approach ( inclusion if > 10% effect on point estimate ) ; none were retained . comparisons between groups that were not propensity - matched ( ntm - pd vs. ntm - pi and single - species vs. multispecies ntm - pd ) included all ontario residents with ntm species conditions of interest and were adjusted for age , sex , and covariates used to characterize the cohort in our study . for survival analyses of single - species versus multispecies ntm - pd , we addressed immortal time bias ( time to second species infection inflating survival of patients with multispecies ntm - pd ) using status of single - species versus multispecies ntm as a time - varying covariate . secondary survival analyses excluded patients who died within 30 days after ntm index date , assuming that early death was unrelated to ntm . * matched according to age ( years ) , sex , index date (  90 d ) , and propensity score ( estimating the patient - level likelihood of species - specific ntm pulmonary disease ) value within 0.2  sd of the exposed patient . ntm pulmonary disease was defined as the presence of > 1 positive sputum sample for the same species or 1 positive bronchoscopic or biopsy specimen . controls were persons without ntm matched by age , sex , index date , and propensity score . acg ; adjusted clinical group diagnoses using the acg case mix system ( 16 ) ; bmt , hematopoietic stem cell transplant ; copd , chronic obstructive pulmonary disease ; ed ; emergency department ; gerd , gastresophageal reflux disease ; iqr , interquartile range ; mac , mycobacterium avium complex ; ntm , nontuberculous mycobacteria ; sdm ; standardized difference of the mean ( value of < 0.1 generally considered not significant ) ( 17 ) . range reported because of small cell size ( direct or by inference ) , which in accordance with privacy regulations can not be reported . baseline characteristics not included in the propensity score because of their effect to substantially reduce successful matching of exposed cases with unexposed controls . inclusion of these variables as covariates was explored , but none significantly altered the hazard ratio point estimates . during the 13-year study period , 20,617 ontario residents had incident ntm isolation from respiratory tract specimens : 10,936 ( 53% ) with ntm - pi and 9,681 ( 47% ) with ntm - pd . propensity score matching was successful for 9,967 ( 91% ) ntm - pi patients and 8,469 ( 87% ) ntm - pd patients . compared with matched patients , patients who could not be matched to unexposed controls were older ( ntm - pi , median 74 vs. 64 years , p<0.001 ; ntm - pd , median 72 vs. 70 years , p<0.001 ) and had higher frequencies of underlying conditions with higher mean adjusted clinical group case mix ( 16 ) numbers ( ntm - pi 12.6 vs. 8.9 , p<0.001 ; ntm - pd 12.4 vs. 9.8 , p<0.001 ) ( technical appendix 
 table 1 ) . in addition , unmatched patients had substantially lower survival than did matched patients at 1 year ( 76.1% vs. 91.0% ) and 5 years ( 46.3% vs. 76.0% ) for all ntm - pi and at 1 year ( 75.3% vs. 85.7% ) and 5 years ( 47.7% vs. 65.4% ) for all ntm - pd . we observed small differences in sex distribution by species , whereby ntm - pd with mac and m. abscessus was seen more commonly in female patients and the other ntm species were seen more commonly in male patients ( table 1 , 2 ; technical appendix 
 tables 24 ) . combining all species , the median ( interquartile range ) age ranged from 60 ( 4374 ) to 70 ( 5878 ) years for the different species condition groups and for combining species was 65 ( 4977 ) years for ntm - pi and 70 ( 5878 ) years for ntm - pd . patients had a high prevalence of underlying conditions by adjusted clinical group numbers ( 7.310.1 ) , including asthma ( 25%36% ) , chronic obstructive pulmonary disease ( copd ; 25%52% ) , diabetes ( 12%24% ) , chronic kidney disease ( 3%8% ) , and gastresophageal reflux disease ( 11%20% ) , ranging by species * matched according to age ( years ) , sex , index date (  90 d ) , and propensity score ( estimating the patient - level likelihood of species - specific ntm pulmonary isolation ) value within 0.2  sd of the exposed patient . controls were persons without ntm matched by age , sex , index date , and propensity score . acg , adjusted clinical group diagnoses using the acg case mix system ( 16 ) ; bmt , hematopoietic stem cell transplant ; copd , chronic obstructive pulmonary disease ; ed , emergency department ; gerd , gastresophageal reflux disease ; iqr , interquartile range ; mac , mycobacterium avium complex ; ntm , nontuberculous mycobacteria ; sdm , standardized difference of the mean ( value < 0.1 generally considered not significant ) ( 17 ) . range reported because of small cell size ( direct or by inference ) , which according to privacy regulations can not be reported . baseline characteristics not included in the propensity score because of their effect to substantially reduce successful matching of exposed cases with unexposed controls . inclusion of these variables as covariates was explored , but none significantly altered the hazard ratio point estimates . number of events in year before index date . * comparisons between all registered ontario residents with incident species - specific ntm isolation and ntm disease respectively ; matching not required for this analysis , and so adjustment was made for all covariates of interest . ntm disease was defined as > 1 positive sputum for the same species or 1 positive bronchoscopic or biopsy specimen . mac , mycobacterium avium complex ; ntm , nontuberculous mycobacterium ; ref , reference ; smr , standardized mortality ratio .  standardized by sex and age in 5-y strata using data for the ontario population . adjusted for sex , age , income quintile , location , adjusted clinical group case mix system , baseline underlying conditions ( asthma , chronic obstructive pulmonary disease , diabetes , hiv infection , rheumatoid arthritis , chronic kidney disease , gastresophageal reflux disease , bronchiectasis , interstitial lung disease , cystic fibrosis , prior tuberculosis , lung cancer , solid organ transplantation or bone marrow transplantation ) , health use ( number of hospitalizations and emergency department visits in year before index date ) , and ntm disease diagnosis during follow - up as time - varying covariate ( for ntm isolation group only ) . kaplan - meier plots for any ntm ( ntm - pd or ntm - pi ) , including both matched and unmatched patients , by species group , revealed apparently distinct death rates ; survival was highest for patients with m. abscessus and lowest for patients with m. kansasii ( figure ) . in this crude survival comparison , uncontrolled for age , sex , or any other variables , we found a statistically significant difference among curves ( p<0.001 , log - rank ) and significant differences in most pairwise comparisons between species . kaplan - meier survival curves for any pulmonary ntm isolation , by species group , ontario , canada , 20012013 . there is a statistically significant difference among curves ( p<0.001 , log - rank ) in crude survival comparison , uncontrolled for any other variables . differences between individual species pairs statistically significant ( p<0.00005 ) for all pairs except mycobacterium abscessus versus m. fortuitum ( p = 0.19 ) , m. abscessus versus mycobacterium avium complex ( p = 0.14 ) , and m. fortuitum versus mycobacterium avium complex ( mac ) ( p = 0.50 ) . compared with age- , sex- , and propensity - matched unexposed controls , 1- and 5-year survivals were numerically lower for patients with ntm in all groups , regardless of species or condition ( ntm - pi or ntm - pd ) ( table 3 ) . hazard ratios ( hrs ) for death were elevated for all species  condition groups , but those for m. abscessus isolation ( hr  1.39 , 95% ci 0.942.07 ) , and m. fortuitum disease ( hr  1.25 , 95% ci 0.961.63 ) were not statistically significant . * matched by age ( years ) , sex , index date (  90 d ) , and propensity score ( estimating the patient - level likelihood of species  condition combinations ) value within 0.2  sd of the exposed patient . ntm disease was defined as > 1 positive sputum for the same species or 1 positive bronchoscopic or biopsy specimen . controls were persons without ntm matched by age , sex , index date , and propensity score . hr , hazard ratio ; mac , mycobacterium avium complex ; ntm , nontuberculous mycobacterium ; ref , referent . as illustrated by the standardized mortality ratios , adjusted for sex and 5-year age stratum , death rates were increased above expected for the ontario general population for all groups compared ( table 4 ) . in adjusted comparisons , patients with ntm - pd ( vs. ntm - pi ) had higher death rates for all species combined , as well as for mac and m. xenopi individually ( table 4 ) . for the other species groups , although the hrs were similar in magnitude to that for mac , death rates were not significantly higher . compared with the 9,061 patients who had single - species ntm - pd , the 620 patients with multispecies ntm - pd ( any combination of ntm species ) had higher rates of death ( hr  1.19 , 95% ci 1.041.34 ) . death rates also were higher for the subgroup of mac plus m. xenopi ( n = 354 ) versus either species alone ( n = 8,059 ) ( hr  1.23 , 95% ci 1.041.45 ) . the sample size was inadequate to assess other species combinations . in the multivariable analysis of baseline factors for association with death among all patients with incident ntm - pd ( matched and unmatched patients ) , increasing age , male sex , low income , and underlying conditions were all associated with reduced survival ( table 5 ) . compared with mac ( reference species group ) , the results of secondary survival analyses that excluded patients who died within 30 days did not differ significantly from any primary survival analyses . * multivariable cox proportional hazards model including all 9,681 registered ontario residents with incident ntm pulmonary disease ( > 1 positive sputum sample for the same species or 1 positive bronchoscopic or biopsy specimen ) . no matching required for this analysis , and so all covariates of interest were assessed . acg , adjusted clinical group ; copd , chronic obstructive pulmonary disease ; gerd , gastresophageal reflux disease ; iqr , interquartile range ; mac , mycobacterium avium complex ; ntm , nontuberculous mycobacteria . adjusted for sex , age , income quintile , location , acg case mix system , baseline underlying conditions ( asthma , copd , diabetes , hiv , rheumatoid arthritis , chronic kidney disease , gerd , bronchiectasis , interstitial lung disease , cystic fibrosis , prior tuberculosis , lung cancer , solid organ transplantation or bone marrow transplantation ) , health use ( number of hospitalizations and emergency department visits in year before index date ) , and ntm disease diagnosis during follow - up as time - varying covariate ( for ntm isolation group only ) .  totals do not add to 100% because of missing income data in 0.4% of patients   residential setting characterized by rural index of ontario ( 19 ) . our population - based cohort study matched > 18,000 patients who had microbiologically confirmed pulmonary ntm to unexposed controls and clearly demonstrates an increased risk for death with both ntm - pd and ntm - pi . the veracity of this prognostic information is supported by the rigorous survival comparison with unexposed persons matched by age , sex , and the propensity to have ntm . the relatively small sample sizes might account for the fact that we did not observe a significant risk for death in some individual subgroups ( ntm - pi with m. abscessus and ntm - pd with m. fortuitum ) compared with unexposed controls . previous studies demonstrated high rates of death with ntm ( 711 ) , but none compared with matched population - based controls . in addition , most prior studies comprised patients from ntm clinics , which permitted careful clinical characterization but most likely led to substantial bias in patient selection ( 7,8,10 ) . although our 5-year mortality estimates ( 26.6% for ntm - pi and 36.9% for ntm - pd ) were of generally similar magnitude to prior studies ( 711 ) , parsing those studies by cohort type reveals that those comprising single ntm clinics tended to report lower rates of death ( 7,8,10 ) . in the single - clinic study from the united states , which had the lowest 5-year death rate of 18% ( 10 ) , the median age at diagnosis was 55 years , compared with 70 years in our study , which probably explains much of the difference in death . the 2 single - clinic studies from japan , comprising exclusively patients with mac pulmonary disease ( mac - pd ) , reported 5-year death rates of 23.1% and 23.9% ( 7 ) , compared with 33.5% for mac - pd patients in our study , despite similar ages among the 3 studies . in 1 of the studies , treated mac - pd patients had a 5-year risk for death of 22.2% , whereas untreated chronic mac - pd patients had a 5-year risk for 33.3% ( 8) , similar to the patients in our study . perhaps most mac - pd patients in ontario have untreated chronic disease , whereas patients in ntm clinics are more likely to be treated , which might reduce their risk for death . a comprehensive population - based study from denmark observed death rates of 39.7% for mac - pd and 51.0% for m. xenopi disease , compared with 36.3% and 43.2% in our study . the higher rates of death in the denmark study are interesting considering that the cohort was younger and had a smaller proportion of patients with copd , diabetes , and renal disease . however , because the denmark study did not provide detailed clinical characteristics and comprised approximately one third m. gordonae patients ( 11 ) , comparing that cohort with the cohort in our study is difficult . despite methodologic differences , the odds ratio ( or ) for death in a medicare - based study in the united states ( or  1.4 , 95% ci 1.31.6 ) ( 3 ) was similar to our hr for death in survival analysis ( hr  1.63 , 95% ci 1.561.70 ) . the us study comprised only patients who were > 65 years , not enrolled in a health maintenance organization , and identified with ntm infection using codes from the international classification of diseases , ninth revision ( icd-9 ) . restricting our cohort to patients > 65 years of age would exclude > 37% of all patients with ntm - pd . although the use of icd-9 codes to identify patients with ntm infection has not been validated , this method appears to be specific but relatively insensitive ( 20 ) , introducing bias depending on characteristics of ntm - infected patients not detected by this method . the risk for death we observed with ntm - pd was generally greater than with ntm - pi , which was significant for all species combined , mac , and m. xenopi . the lack of a significant difference in survival between ntm - pd and ntm - pi for the other species might have reflected the relatively small number of cases . our results are consistent with findings in the population - based study from denmark ( 11 ) . in the denmark study , 709 patients with 1 positive specimen tended to survive longer than the 238 patients with 2 or 3 positive specimens , who in turn tended to survive longer than the 335 patients who had > 3 positive specimens ( p = 0.07 ) . the difference in statistical significance probably is due to sample size because our study had far more patients . the significantly higher death rate for patients who had even 1 positive sputum specimen for mac or m. xenopi is of particular interest . in some cases a positive sputum sample could be insignificant , representing contamination or transient presence of the organism , which would presumably not be associated with increased risk for death . in other cases , a positive sputum sample might represent the 1-time identification of a chronically present organism , which might or might not be causing significant disease . in this latter group , the presence of only 1 positive sample could be explained either by inadequate sampling or difficulty in identifying a true pathogen present in low numbers . either way , some patients designated as having ntm - pi probably had true disease . the lack of data about negative cultures precludes further exploration of this issue . as with others findings , we identified variable survival among patients with different ntm species . our unadjusted analyses are consistent with the denmark study ; patients with m. abscessus and m. fortuitum had lower death rates than patients with mac , who in turn had lower death rates than patients with m. xenopi ( 11 ) . however , in our adjusted analysis , survival with m. abscessus and m. fortuitum pulmonary disease did not differ from survival with mac disease . the worse crude survival observed with m. xenopi and m. kansasii persisted in adjusted analyses only for m. xenopi . the reason for the worse prognosis with m. xenopi , despite adjustment for age , sex , and underlying conditions , is not clear . there could be residual confounding related to cavitation and copd , both commonly present with m. xenopi disease . patients with m. xenopi disease have far higher rates of cavitation than do patients with mac ( 46% vs. 16% ; p = 0.01 ) ( 21 ) , and cavitation is consistently associated with death ( 7,8,10 ) . m. xenopi is also associated with copd ( 11 ) , and although both studies adjusted for copd , the severity of copd could be greater among patients with m. xenopi infection . inadequately measured covariates could potentially explain the poor survival among patients infected with m. xenopi . the lower survival observed with m. kansasii ( compared with mac ) in unadjusted analysis , which did not persist in adjusted analysis , is most likely explained largely by the high proportion of male patients , copd , and hiv infection among m. kansasii patients . regardless , the adjusted analysis did not find that m. kansasii was associated with higher death rates than mac , perhaps as expected because the former is believed to be the most readily curable of the ntm pulmonary pathogens ( 5 ) , despite a high prevalence of cavitary disease ( 22 ) . the analysis of risk factors for death among patients with ntm - pd provided results generally consistent with those of previous studies . as in our study , increasing age ( 7,11 ) , male sex ( 3,7,11 ) , and underlying conditions ( 3,11 ) are repeatedly identified as risk factors for death . other factors , including copd , asthma , bronchiectasis , and other diseases , have been less studied . our finding that copd is associated with death ( hr  1.38 , 95% ci 1.291.48 ) seems plausible , not only because of the death intrinsic to copd , but also because fibrocavitary ntm - pd develops more often in patients with copd ( 5 ) , and cavitation is associated with lower survival ( 7,8,10 ) . our finding that asthma is associated with a lower risk for death ( hr  0.89 , 95% ci 0.830.95 ) is perhaps surprising ; it might be confounded by an association between asthma and nodular bronchiectatic ntm - pd , which has a better prognosis than cavitary disease ( 7,8,10 ) . although 1 previous study reported that ntm - pd patients with asthma had a higher risk for death ( or  1.7 , 95% ci 1.12.7 ) ( 3 ) , ntm - pd was identified by icd-9 coding , which might overlook a large proportion of ntm - pd and thus introduce bias . the presence of bronchiectasis in ntm - pd presumably makes cavitation less likely to be present , and so our finding of lower death rates in the presence of bronchiectasis ( hr  0.77 , 95% ci 0.700.84 ) seems plausible and is consistent with a prior report ( 3 ) . the significant associations that we observed between death and interstitial lung disease , lung cancer , hiv infection , cystic fibrosis , and bone marrow transplantation all seem plausible given the risks for death generally conferred by these clinical factors . some underlying conditions undoubtedly emerged after the index date in affected patients and in unexposed controls . we elected to ignore any mortality effect of subsequently emerging underlying conditions , favoring the development of a mortality estimate based on information at the time of diagnosis . given the high frequency of bronchiectasis in ntm - pd ( 5 ) , it is noteworthy that bronchiectasis in our study was uncommon , measured as 8.5% and 6.1% among matched ntm - pd and ntm - pi patients , respectively , and 14.2% and 10.5% among all ntm - pd and ntm - pi patients . our reliance on a simple unvalidated diagnostic code definition probably failed to identify the presence of bronchiectasis in many patients . the underappreciation of bronchiectasis might have been greater among the groups of patients with ntm , wherein one would expect a high proportion of bronchiectasis . accordingly , assuming that bronchiectasis per se increases death , our death estimates in ntm groups might be overestimates . first , because of an absence of clinical data , our definition of ntm - pd is based exclusively on microbiology , which probably misclassifies some patients with ntm colonization as having disease . nevertheless , this misclassification rate most likely is small because microbiological - based definitions of ntm - pd exhibit high accuracy ( 11,20,23,24 ) . furthermore , the resulting effect of diagnostic misclassification would probably not significantly alter our findings . misclassifying some patients with ntm - pi as ntm - pd would be expected to incorrectly place some patients with milder illness into the ntm - pd group and result in an attenuated apparent death attributable to ntm - pd . therefore , the ntm - pd death rate is perhaps somewhat greater than we observed . there could be a stage migration phenomenon ( 25 ) , by selective misclassification of the  more severe ntm - pi as ntm - pd , apparent death could be reduced in both ntm - pi and ntm - pd . the same effect is also at play in our definition of ntm - pd with respect to the time between a first and a second positive sputum culture . rather than arbitrarily defining a time period between a first and a second positive sputum culture , which would separate patients with initial ntm - pi progressing to ntm - pd  and  initial ntm - pd ,  we defined all patients with 2 positive sputa at any time during the study period as having ntm - pd . the index date was always the date of the first positive sputum , which introduces an immortal time bias in the patients with ntm - pdd , defined as the time between the first and second positive sputum sample and leads to some underestimation of the associated mortality of ntm . second , the lack of comprehensive medication information precludes assessing the effect of antimycobacterial treatment on survival and limits our ability to control for severity of some comorbid illnesses , such as copd . third , we were unable to ascertain cause of death for patients in our study . two studies of mac - pd from separate ntm clinics in japan reported that most patients died of causes other than their ntm - pd ( 7,8 ) , whereas a study from 1 ntm clinic in the united states found that most deaths were ntm - related ( 10 ) . we suspect that the higher proportion of deaths from ntm in the us study occurred because the patients were substantially younger at diagnosis , making deaths from other causes much less likely . fourth , our propensity score matching was unsuccessful for 9% of ntm - pi patients and 13% of ntm - pd patients , and unmatched patients were older and had more underlying conditions . although the effect of omitting these patients on our calculated hrs is not clear , an underestimation of the true risk for death is likely , in that unmatched ntm patients had substantially lower survival than did matched ntm patients . fifth , the lack of data on patients with negative mycobacterial cultures precluded using such patients as unexposed controls . other factors detected by clinicians and triggering a request to collect respiratory specimens for mycobacterial studies might have confounded our mortality estimates . in summary , patients with ntm - pd have significantly lower survival than do appropriately matched population controls . this increasingly common health problem is clearly associated with not only substantial illness but with death as well . further work should clarify the mortality effects of co - existing conditions , such as copd , asthma , and bronchiectasis , infection with different ntm species , especially m. xenopi , specific antimicrobial treatment of the ntm infection , and cause of death among ntm patients .
survival implications of nontuberculous mycobacterial pulmonary disease ( ntm - pd ) and ntm pulmonary isolation without disease ( ntm - pi ) are unclear . 
 to study deaths associated with ntm - pd and ntm - pi and differences in survival between them , we conducted a population - based cohort study of persons with microbiologically defined ntm - pd or ntm - pi diagnosed during 20012013 in ontario , canada . 
 we used propensity score matching and cox proportional hazards models to compare survival . among 9,681 ntm - pd patients and 10,936 ntm - pi patients , 87% and 91% , respectively , 
 were successfully matched with unexposed controls . 
 both ntm - pd and ntm - pi were associated with higher rates of death for all species combined and for most individual species . 
 compared with ntm - pi , ntm - pd was associated with higher death rates for all species combined , mycobacterium avium complex , and m. xenopi . ntm - pd and ntm - pi were significantly associated with death , ntm - pd more so than ntm - pi .