Pulmonary Nontuberculous Mycobacterial Disease Prevalence and Clinical Features
Pulmonary Nontuberculous Mycobacterial Disease Prevalence and Clinical Features
Pulmonary Nontuberculous Mycobacterial Disease Prevalence and Clinical Features
Oregon Health & Science University and 2Oregon Public Health Division, Portland, Oregon
Rationale: Respiratory specimens with nontuberculous mycobacteria (NTM) are increasingly common; however, pulmonary disease prevalence is unknown. Objectives: To determine the disease prevalence, clinical features, and risk factors for NTM disease, and to examine the predictive value of the microbiologic criteria of the American Thoracic Society (ATS)/ Infectious Diseases Society of America (IDSA) pulmonary NTM case denition for true NTM disease. Methods: We identied all Oregon residents during 20052006 with at least one respiratory mycobacterial isolate. From a populationbased subset of these patients, we collected clinical and radiologic information and used the ATS/IDSA pulmonary NTM disease criteria to dene disease. Measurements and Main Results: In the 2-year time period, 807 Oregonians had one or more respiratory NTM isolates. Four hundred and seven (50%) resided within the Portland metropolitan region, among which 283 (70%) had evaluable clinical records. For those with records, 134 (47%) met ATS/IDSA pulmonary NTM disease criteria for a minimum overall 2-year period prevalence of 8.6/ 100,000 persons, and 20.4/100,000 in those at least 50 years of age within the Portland region. Case subjects were 66 years of age (median; range, 1292 yr), frequently female (59%), and most with disease caused by Mycobacterium avium complex (88%). Cavitation (24.5%), bronchiectasis (16%), chronic obstructive pulmonary disease (28%), and immunosuppressive therapy (25.5%) were common. Eighty-six percent of patients meeting the ATS/IDSA microbiologic criteria for disease also met the full ATS/IDSA disease criteria. Conclusions: Respiratory NTM isolates frequently represent disease. Pulmonary NTM disease is not uncommon, particularly among elderly females. The ATS/IDSA microbiologic criteria are highly predictive of disease and could be useful for laboratory-based NTM disease surveillance. Keywords: nontuberculous mycobacteria; pulmonary disease; disease prevalence; epidemiology; bronchiectasis
AT A GLANCE COMMENTARY
Scientic Knowledge on the Subject
There is limited information regarding the epidemiology and prevalence of pulmonary nontuberculous mycobacteria (NTM) disease in the United States.
What This Study Adds to the Field
Respiratory NTM isolates frequently represent disease. Pulmonary NTM disease is not uncommon, particularly among elderly females. The American Thoracic Society/ Infectious Diseases Society microbiologic criteria are highly predictive of disease and could be useful for laboratorybased NTM disease surveillance.
Nontuberculous mycobacteria (NTM) cause a variety of infections in humans, including chronic, debilitating pulmonary disease among elderly persons. Although the epidemiology of tuberculosis is well described, the prevalence and epidemiology of NTM disease in the United States is largely unknown. There is widespread belief among experts that pulmonary NTM disease is increasingly prevalent and perhaps more prevalent than tuberculosis, although to date, there have been no large population-based studies that document its prevalence or
(Received in original form March 31, 2010; accepted in nal form May 27, 2010 ) Supported by an Agency for Healthcare Research and Quality (AHRQ) grant (1K08HS017552-01) (K.L.W.). Correspondence and requests for reprints should be addressed to Kevin L. Winthrop, M.D., M.P.H., CEI/OHSU, 3375 SW Terwilliger Blvd., Portland, OR 97239. E-mail: Winthrop@ohsu.edu
Am J Respir Crit Care Med Vol 182. pp 977982, 2010 Originally Published in Press as DOI: 10.1164/rccm.201003-0503OC on May 27, 2010 Internet address: www.atsjournals.org
associated risk factors (1). The clinical characteristics and comorbidities associated with this disease have largely been reported in the form of institutional case series from highly specialized treatment centers. These series suggest that bronchiectasis and other chronic lung disease are prevalent in patients with pulmonary NTM (1). Given the specialized nature of such tertiary referral centers, and the severity of NTM disease often treated in those centers, it is unclear whether their reported patient case characteristics mirror those with disease in the general population. NTM thrive within the biolm of municipal water systems and likely infect susceptible hosts via aerosolization (2, 3). In this manner, NTM represent a potential public and environmental health threat to those at risk. Because NTM are environmental organisms capable of contaminating respiratory specimens, patients must meet specic clinical, radiologic, and microbiologic criteria for pulmonary disease, including the following: (1) respiratory or constitutional symptoms, (2) radiologic ndings of reticular, interstitial, nodular inltrate, or cavitation, and (3) at least one bronchoalveolar lavage specimen, or in the case of sputum, repeated (two or more) specimens yielding identical NTM species (1). Accordingly, it is understandable why estimates of pulmonary NTM disease are difcult to obtain in the United States or most nations. Prior studies have reported increasing incidence of NTM isolation within populations, but have not been able to examine the clinical records of such patient to distinguish disease from colonization (1). We performed a statewide laboratorybased surveillance project for NTM in Oregon, whereby we captured demographic and microbiologic information for every Oregon resident with respiratory NTM isolates during a 2-year time period, 2005 2006 (4). We subsequently undertook the current study to review the clinical records of a population-based subset of these patients; those residing in the Portland Tri-County metropolitan region (n . 1.5 million) (5). We sought to determine the pre-
978
VOL 182
2010
valence of NTM disease in this population, dene the clinical characteristics of pulmonary NTM disease, evaluate potential disease risk factors, and validate the use of the microbiologic criteria of the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA) case denition alone to estimate disease prevalence; a potential powerful tool for public health authorities with which to track disease trends by laboratory-based surveillance.
METHODS
After the Oregon Public Health Department approved this public health surveillance project, we identied all Oregon residents during 2005 and 2006 with one or more respiratory NTM isolate(s) (4). From these data, we used resident ZIP codes to identify all such patients living in the TriCounty region of Portland, Oregon, and then sought to review their clinical records. Most patients received care at one of the regions ve medical care systems, whereas a small minority received care at county clinics. Because county clinics were geographically widespread, lacked radiologic facilities, and lacked electronic medical records, we chose to review all patient records from the ve medical systems (i.e., Oregon Health & Science University, Portland Veteran Affairs Medical Center, Kaiser-Permanente Northwest, Legacy Healthcare, and Providence Healthcare). To better understand trends outside the Portland region, we also reviewed clinical records in a less urban county (Marion) in the central Willamette Valley 50 miles south of Portland. For each patient, we evaluated electronic clinical, microbiologic, and radiologic records dated within the 2-year study time period. Information from records before or after the study time period was not collected. We collected symptom, treatment, and comorbidity data from physician notes, radiographic ndings from radiologist reports, and concomitant medication information from physician notes and medication elds of electronic records from visits associated with each patients respiratory culture. During record review, some patient medical records lacked recorded symptom or radiologic information. We considered such patients not clinically evaluable. Patients with clinical records containing symptom, radiographic, and microbiologic information were considered clinically evaluable and dened either as case or noncase according to the full 2007 ATS/IDSA pulmonary NTM case denition (1). We calculated period prevalence of disease for the Portland Tri-County region, using an age-adjusted population denominator provided by Oregon State census data (5). All data were entered into an Access Database (Microsoft, Redmond, WA) and analyzed with Epi Info (Centers for Disease Control and Prevention, Atlanta, GA). Univariate comparisons were made to evaluate differences between cases and noncases. We used x2 and Fisher P values to evaluate observed differences. Comparison of medians (age) was done by Mann-Whitney/Wilcoxon two-sample test.
Patients meeting case criteria (n 5 184) were 66 years of age (median; range, 1292 yr) and 109 (59%) were female. Nearly one-quarter of pulmonary NTM case subjects presented with cavitation, and 31 (17%) had effusions noted on imaging (Table 1). Compared with males, female case subjects were older (median age, 68 vs. 62 yr; P 5 0.01), signicantly less likely to present with pulmonary effusion (12 vs. 24%; relative risk [RR], 0.5; 95% condence interval [CI], 0.30.95; P 5 0.03), and less likely to present with cavitary disease, although this difference was not statistically signicant (20 vs. 31%; P 5 0.07 [Table 2]). Comorbid conditions were common among case subjects and included chronic obstructive pulmonary disease (COPD), lung cancer, and bronchiectasis (Table 3). Among case subjects, COPD was less common among female case subjects (22 vs. 37%; RR, 0.7; 95% CI, 0.51.0; P 5 0.02), whereas bronchiectasis showed a trend toward being associated with female case subjects (20 vs. 11%; RR, 1.9; 95% CI, 0.94.0; P 5 0.06). Onequarter (n 5 47) of patients were taking systemic or inhaled immunosuppressive medication at the time of NTM isolation (Table 3). Oral prednisone alone or in combination with other agents (n 5 29) accounted for nearly two-thirds of the immunosuppressive medications noted. There were 14 patients using inhaled corticosteroids, 5 of whom were also taking oral prednisone concomitantly. Smaller numbers of patients were using methotrexate (n 5 4), the biologic therapies iniximab, adalimumab, and rituximab (n 5 1 each), or chemotherapy (n 5 1). When comparing differences between those patients with evaluable records who met disease criteria versus those who did not, few differences were found. Patients meeting criteria were more likely to be female (RR, 1.3; 95% CI, 1.01.5; P 5 0.01) and to have radiographic evidence of cavitary disease (RR, 2.5; 95% CI, 1.54.2; P , 0.01) (Table 1), but were otherwise similar regarding age and medical comorbidities (Table 3). M. avium was etiologic in most cases (n 5 161, 87.5%). Patients with disease due to rapidly growing mycobacteria (RGM) most frequently had isolates identied as M. abscessus (n 5 6) or M. abscessus/chelonae (n 5 4). A small number of cases were due to unspeciated or other mycobacteria (Figure 1). Patients with pulmonary RGM disease were signicantly more likely to have underlying gastroesophageal reux disease noted (RR, 4.8; 95% CI, 1.812.9; P 5 0.01), There were no other differences regarding sex or comorbidities noted between RGM and Mycobacterium avium-intracellulare cases, although we had limited power for such comparisons.
RESULTS
Statewide, there were 807 Oregonians with one or more respiratory NTM isolates during the 2-year time period, and 407 (50%) of these patients resided within the Tri-County Portland metropolitan region. Of these 407 patients, 283 (70%) had full clinical records available for review. One hundred and thirtyfour (47%) of those with evaluable clinical records met ATS/ IDSA criteria for pulmonary NTM. Statewide, including our evaluation of Marion County residents with evaluable clinical records (n 5 30) and those patients with records who received medical care within the Tri-County region but who resided elsewhere in the state (n 5 58), a total of 184 (50%) of 371 patients with clinically evaluable records met the ATS/IDSA criteria for pulmonary disease. Patients meeting disease criteria who lived within the Tri-County region (n 5 134) were similar regarding age, sex, comorbid diseases, therapy, and etiology to those additional 50 patients meeting disease criteria who lived outside the Tri-County region. Accordingly, to simplify presentation of our clinical results, we have reported case-related data for all 184 cases meeting disease criteria.
TABLE 1. CHARACTERISTICS OF PATIENTS WITH CLINICALLY EVALUABLE RECORDS THAT MET ATS/IDSA PULMONARY NTM DISEASE CRITERIA IN THE 2-YEAR STUDY TIME PERIOD, COMPARED WITH PATIENTS WITH ONE OR MORE RESPIRATORY NTM ISOLATES WHO DID NOT MEET CRITERIA
Conrmed Case (n 5 184) Age (median) Female Cavitary Effusion NTM therapy 66 109 45 31 62 (1292) (59%)* (24.5%)* (17%) (37%)* Did Not Meet ATS/IDSA Criteria (n 5 187) 65 88 18 44 14 (2093) (47%)* (10%)* (23.5%) (8%)*
Denition of abbreviations: ATS/IDSA 5 American Thoracic Society/Infectious Diseases Society; NTM 5 nontuberculous mycobacteria. * Denotes P < 0.05 for comparison between columns. Cavitation noted on either chest radiograph or computed tomography (CT). For cases, cavitation was noted in 18 (10%) and 40 (21.5%) of chest radiograph and CT exams, respectively. For non-cases, cavitation was noted in 8 (4%) and 14 (7.5%) of chest radiographs and CT scans, respectively.
979 TABLE 2. COMPARISON OF PULMONARY NTM DISEASE CHARACTERISTICS BETWEEN MALE AND FEMALE CASE SUBJECTS
Female (n 5 109) Age (median) Cavitation Effusion COPD Bronchiectasis Immunosuppressive Tx Previous TB 68 yr* 22 (20%) 13 (12%)* 24 (22%)* 22 (20%) 32 (29%) 8 (7%) Male (n 5 75) 62 yr* 22 (31%) 18 (24%)* 28 (37%)* 8 (11%) 15 (20%) 9 (12%)
Denition of abbreviations: COPD 5 chronic obstructive pulmonary disease; TB 5 tuberculosis; Tx 5 treatment. * Denotes P , 0.05 for comparison between columns designated male and female. Cavitation noted on either chest radiograph or computed tomography. Previous TB included history of latent TB infection (n 5 11), prior active TB disease (n 5 3), and history of unknown active versus latent TB (n 5 3).
Of all patients with clinically evaluable records (n 5 371), there were 214 (58%) patients that met the microbiologic component of the full ATS/IDSA disease criteria. Of these 214 patients, 183 (86%) met the full ATS/IDSA disease criteria, indicating the positive predictive value of the microbiologic component alone to be 86% in patients with records available to review (one additional patient met full disease criteria based on tissue pathology and one positive sputum sample and was therefore not detected on the basis of the microbiologic criteria alone). Among Tri-County residents, where we had a complete denominator of residents and could therefore fully evaluate differences between those residents with and without clinically evaluable records, patients with full clinical records present were signicantly older (median age, 66 vs. 56 yr; P , 0.01), more likely to be female (55 vs. 48%; RR, 1.2; 95% CI, 0.91.4; P 5 0.08), more likely to meet the ATS microbiologic criteria (56 vs. 39%; RR, 1.5; 95% CI, 1.11.8; P , 0.01), and much less likely to have a nonspeciated isolate (36 [27%] vs. 19 [67%]; RR, 0.20; 95% CI, 0.10.4). One hundred and fty-nine (77%) of the 206 Tri-County residents who met microbiologic criteria for disease had full clinically evaluable records present.
Disease Prevalence
Figure 1. Mycobacterial etiology of conrmed pulmonary nontuberculous mycobacteria (NTM) disease, Oregon 20052006 (n 5 184). *M. abscessus/chelonae includes patients with isolates labeled as M. abscessus (n 5 6), M. abscessus/chelonae (n 5 4), and M. chelonae (n 5 1). Other includes M. simiae (n 5 2), M. goodii (n 5 1), M. fortuitum (n 5 1), M. gordonae (n 5 1), M. xenopi (n 5 1), and M. kansasii (n 5 1). MAC 5 Mycobacterium avium complex.
case subjects met the ATS/IDSA case denition for disease, representing a 2-year period prevalence of 8.6/100,000 in the general population. After adjusting for age, the 2-year period prevalence among those at least 50 years old was 20.4/100,000 at minimum. Of the 124 patients for whom clinical records were not available for review, an additional 48 (39%) met the microbiologic criteria of the ATS case denition and could have been cases (35 of these 48 were 50 yr of age or older). If 85% of these were in fact true case subjects, as based on the validated positive predictive value of the ATS microbiologic criteria, then adding these likely case subjects to those conrmed case subjects would give an upper limit 2-year prevalence estimate of 11.2/100,000 in the general population and 25.7/100,000 in those at least 50 years old. By contrast, the 2year incidence rate for tuberculosis (TB) in those at least 50 years old in the Tri-County area during the study time period was 6.7/100,000.
Using the Portland Tri-County census data for the years 2005 2006, we calculated a minimal estimate of 2-year period prevalence. The average Tri-County population for the 2-year study time period was 1,556,540 residents, among whom we identied 407 potential case subjects. Of these, at minimum, 134
TABLE 3. MEDICAL COMORBIDITIES AMONG PATIENTS WITH FULLY EVALUABLE CLINICAL RECORDS FOR THOSE WITH CONFIRMED PULMONARY NTM DISEASE (N 5 184) COMPARED WITH THOSE WHO DID NOT MEET CASE CRITERIA (N 5 187) DURING THE 2-YEAR STUDY TIME PERIOD
Conrmed Case (n 5 184) Bronchiectasis COPD DM Lung cancer Immunosuppressive Tx RA GERD 30 52 13 12 47 5 15 (16%)* (28%) (7%) (6.5%) (25.5%) (3%) (8%) Did Not Meet ATS/IDSA Criteria (n 5 187) 19 53 16 14 48 5 13 (10%)* (28%) (9%) (7.5%) (26%) (3%) (7%)
DISCUSSION
We have conducted a population-based study of patients with respiratory NTM isolates in Oregon during 20052006. To our knowledge, this is the rst study to determine pulmonary NTM disease prevalence within a population, and the rst to systematically examine the clinicepidemiologic features of disease from a general population. We have documented a minimal 2year NTM pulmonary disease prevalence of 8.6/100,000 in the general population and more than 20/100,000 in those at least 50 years of age. Our results establish that elderly women are disproportionately affected by this disease and that they tend to manifest disease differently than do men; further, underlying lung disease and immunosuppressive therapies are common among cases. Importantly, we have validated the use of the microbiologic component of the ATS/IDSA disease criteria as a surveillance tool for pulmonary NTM disease. Overall, between one-third and one-half of all respiratory NTM isolates in Oregon are indicative of NTM disease. Efforts should be made to monitor trends in this emerging disease. In population-based fashion, we have documented that pulmonary NTM more frequently affect women (610). This is contrary to early case series reports of disease from the United States, and contrary to current European studies suggesting that pulmonary NTM is more strongly associated
Denition of abbreviations: ATS/IDSA 5 American Thoracic Society/Infectious Diseases Society; COPD 5 chronic obstructive pulmonary disease; DM 5 diabetes mellitus; GERD 5 gastroesophageal reux disease; RA 5 rheumatoid arthritis; Tx 5 treatment. * Denotes P < 0.05 for comparison between columns.
980
VOL 182
2010
with males, particularly those with COPD (11, 12). In our study, a high proportion of case subjects had underlying structural lung disease regardless of sex, although COPD was more common among males and bronchiectasis was more common among females. Several notable NTM pulmonary pathogens are missing from Oregon epidemiology, including Mycobacterium xenopi, M. malmoense, and M. kansasii. These pathogens are more prevalent in Europe and perhaps of different pathogenicity, potentially explaining the difference in sex predisposition between the continents (12, 13). Our study also suggests that men and women with NTM often manifest disease differently. Men were more likely to have pleural effusion or COPD, and a trend was observed with female case subjects more likely to be using immunosuppressive drugs or having bronchiectasis. Although we had little power to examine differences between RGM disease and that caused by Mycobacterium avium-intracellulare or other slowly growing mycobacteria, we found gastroesophageal reux disease (GERD) to be signicantly associated with RGM disease. Prior institution-based case-series studies have suggested this association (14), although it is unclear whether GERD is causal in RGM or other NTM disease and our ndings could be explained by potential diagnostic bias. Some investigators speculate that proton pump inhibitors used to treat GERD might increase the ability of mycobacteria to live in the gut and could predispose to RGM or other NTM disease, although evidence of this for M. avium at least in vitro is lacking, and proton-pump inhibitor (PPI) use might simply serve as a marker for more severe GERD (15, 16). Further research is necessary to evaluate the potential causal role of GERD and PPI use in promoting RGM and other mycobacterial pulmonary disease. The pathogenesis of pulmonary NTM is poorly understood. Many female patients with NTM are slender, underweight, and have characteristic features such as scoliosis, pectus defects, hypomastia, or mitral valve prolapse (1, 8). Investigators have described various immune decits that lead to disseminated, but not pulmonary, NTM disease. These deciency states are rare and include IFN-g deciency or autoantibody states and IL-12 deciency (6, 17). Cytokines such as tumor necrosis factor (TNF)-a are known to be essential to granuloma formation and maintenance. Cases of pulmonary NTM have been reported among patients taking drugs that inhibit TNF (1820), and at least one study has suggested that patients with pulmonary NTM have lower levels of TNF expressed by lung immune cells in the presence of NTM challenge as compared with nondiseased control subjects (21). Few patients in our cohort were using anti-TNF drugs; however, a large percentage were using systemic or inhaled corticosteroids, presumably to treat COPD, rheumatoid arthritis, or other chronic diseases commonly noted in our cohort. It is unclear whether prednisone increases the risk of NTM as it does for TB (22), or if the high percentage of immunosuppressive use in this cohort simply reects the high degree of comorbidities in these patients. Although we could nd little background prevalence data for many of these chronic conditions, we believe the rates of COPD and lung cancer observed in our NTM cohort are well above that seen in the general population, even among the elderly. For bronchiectasis, the prevalence in our cohort (16%) far exceeded the background population prevalence in elderly populations (national estimates of 0.27% prevalence among Americans 75 yr or older) (23, 24). It has been hypothesized that the pulmonary architectural defects associated with these conditions impair host response locally and promote the trapping of environmental organisms such as NTM and increase the risk of infection (25, 26). The estimation of pulmonary NTM disease prevalence has previously been elusive. NTM are not reportable pathogens, and
in the case of NTM culture isolation, review of clinical records is necessary to ascertain whether the NTM is clinically meaningful and represents disease. Accordingly, microbiologic criteria for disease have been developed by an expert ATS/IDSA committee (1). These criteria, when present in the context of symptoms and characteristic radiologic abnormalities, suggest that NTM disease is present. We hypothesized that patients meeting the microbiologic criteria would be likely to meet the full disease criteria, given that existing pulmonary symptoms or radiographic abnormalities generally trigger the collection of respiratory specimens. Among patients with clinical records present in our cohort, the microbiologic criteria in fact had high positive predictive value for disease. This may in part be because most of our disease was caused by Mycobacterium avium complex, for which the ATS/IDSA disease criteria are most applicable. For the patients with clinical records lacking, however, it is possible that the positive predictive value of the microbiologic criteria could be lower, although there were many fewer such persons who met the microbiologic criteria and it is unlikely that this would affect our overall calculated positive predictive value substantially. Accordingly, we believe our ndings suggest that future surveillance efforts could be laboratory-based and rely solely on these microbiologic criteria to estimate disease prevalence and monitor disease trends. We were not able to systematically access all patient records before the study time period, so we were unable to distinguish between existing and incident cases. For this reason, we chose to calculate a period prevalence for the 2-year study time period. We believe this calculation likely underestimates the true prevalence for several reasons. First, there were a number of persons who failed to meet the ATS/IDSA microbiologic criteria during the 2-year time period, but who were known to the investigators to have had additional positive respiratory cultures collected either before or after the study time period, which would have allowed them to meet disease criteria. However, because we could not look systematically at data before or after the 2-year study time period for all patients, we did not record such persons as case subjects. Second, among many of the patients with only one sputum examination positive for NTM, there was no evidence in the clinical records that subsequent respiratory evaluations had been performed during the study time period such that these patients did not have the opportunity to meet the case denition. Third, many patients with NTM disease are unable to produce sputum, particularly after beginning antibiotic therapy. It is likely there were such prevalent cases in the state during this time, but that our laboratory-based case-nding failed to identify them. Last, some patients meeting the microbiologic criteria failed to satisfy the full ATS/IDSA disease criteria, primarily because they either lacked radiographic ndings from chest radiographs, a methodology not as sensitive as chest computed tomography, or because they had other conditions (e.g., lung cancer, TB) and it was unclear during our chart review whether they also had NTM disease. In our review of these patients not meeting disease criteria, it is interesting that they were similar in many respects (e.g., age, comorbidities, and underlying lung disease) to their counterparts who satised the criteria. It is likely that at least some of these patients truly had disease. Our study suggests that pulmonary NTM disease is not rare in Oregon, and that it has emerged as a pathogen with important environmental and public health implications. If we apply the 86% predictive value of the ATS/IDSA microbiologic criteria to our statewide microbiology ndings, then the 2-year period prevalence for the entire state is 26.7/100,000 in persons more than 50 years of age (4). This indicates that pulmonary NTM disease occurs several-fold more frequently than tuberculosis
981
(annual incidence rate, 2.5/100,000 during the study time period) (27), and it is likely that at least some of these patients are considered TB suspects before diagnosis, with many undergoing clinical and laboratory assessment within the TB control infrastructure. These county clinics and laboratories are funded for TB control, yet much of their efforts in Oregon, and likely other low-prevalence TB regions, are dominated by NTM. If NTM disease is increasing in prevalence as suggested by the increasing population prevalence of isolates in previous studies (28), then an increasing proportion of TB control dollars are being spent on NTM control. In this regard, NTM represents an important public health issue. Furthermore, and most importantly, NTM appear to represent an environmental health threat for predisposed individuals. These organisms are environmental pathogens not unlike Legionella in many respects, a reportable pathogen for which public and environmental health efforts are made to prevent disease (29). Like Legionella, NTM live in municipal water supply systems, where they are competitors within pipe biolm (2, 30). It is likely that persons are exposed in similar ways to both organisms, via the aerosolization and inhalation of such water, and similarly only a small percentage of exposed persons develop subsequent disease. Interestingly, Legionella is sensitive to chlorination whereas NTM are not, and it is plausible that the steps taken to disinfect our municipal water supply systems over the last several decades have resulted in decreased Legionella concentrations, with corresponding increases in NTM concentrations (31). There are published source exposure investigations of patients with newly diagnosed NTM, whereby NTM isolates from patients and their home or hospital tap water have been found to be genetically identical, suggesting this as the likely source of their infection (3234). Clearly, efforts should be made to better understand issues of NTM pathogen exposure and routes of transmission, disease risk factors, and methods of mitigating the risk of disease should be developed for those at high risk. At present, most of these questions remain unexplored. These efforts will require signicant investment, and will likely require dedicated effort from public and environmental health agencies within this country.
Author Disclosure: K.L.W. received $1,001$5,000 from Genentech in lecture fees, $1,001$5,000 from Wyeth, and $1,001$5,000 from Amgen in lecture fees, $50,001$100,000 from UCB and $10,001$50,000 from Oxford Immunotech in industry-sponsored grants, and more than $100,001 from Agency for Healthcare Research and Quality (AHRQ) in sponsored grants as a K08 career development grant. E.M. does not have a nancial relationship with a commercial entity that has an interest in the subject of this manuscript. B.K. does not have a nancial relationship with a commercial entity that has an interest in the subject of this manuscript. A.M.-O. does not have a nancial relationship with a commercial entity that has an interest in the subject of this manuscript. C.M. does not have a nancial relationship with a commercial entity that has an interest in the subject of this manuscript. M.C. does not have a nancial relationship with a commercial entity that has an interest in the subject of this manuscript. A.S. does not have a nancial relationship with a commercial entity that has an interest in the subject of this manuscript. K.H. received $50,001$100,000 in sponsored grants from the Centers for Disease Control as part of her salary as the TB control ofcer for Oregon.
References
1. Grifth DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, et al.; American Thoracic Society; Infectious Disease Society of America. An ofcial ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007;175:367416. 2. Falkinham JO. Epidemiology of infection by nontuberculous mycobacteria. Clin Microbiol Rev 1996;9:177215. 3. Thomas V, McDonnell G. Relationship between mycobacteria and amoebae: ecological and epidemiological concerns. Lett Appl Microbiol 2007;45:349357.
4. Cassidy MP, Hedberg K, Saulson A, McNelly E, Winthrop KL. Nontuberculous mycobacterial disease prevalence and risk factors: a changing epidemiology. Clin Infect Dis 2009;49:e124e129. 5. Population Research Center, Portland State University. Oregon Population Report 2005 and 2006 (accessed July 2010). Available from http://www.pdx.edu/prc/annual-oregon-population-report 6. Kim RD, Greenber DE, Ehrmantraut ME, Guide SV, Ding L, Shea Y, Brown MR, Chernick M, Steagall WK, Glasgow CG, et al. Pulmonary nontuberculous mycobacterial disease: prospective study of a distinct preexisting syndrome. Am J Respir Crit Care Med 2008;178:10661074. 7. Prince DS, Peterson DD, Steiner RM, Gottlieb JE, Scott R, Israel HL, Figueroa WG, Fish JE. Infection with Mycobacterium avium complex in patients without predisposing conditions. N Engl J Med 1989;321: 863868. 8. Iseman MD, Buschman DL, Ackerson LM. Pectus excavatum and scoliosis: thoracic anomalies associated with pulmonary disease caused by Mycobacterium avium complex. Am Rev Respir Dis 1991; 144:914. 9. Grifth DE, Girard WM, Wallace RJ Jr. Clinical features of pulmonary disease caused by rapidly growing mycobacteria: an analysis of 154 patients. Am Rev Respir Dis 1993;147:12711278. 10. Bodle EE, Cunningham JA, Della-Latta P, Schluger NW, Saiman L. Epidemiology of nontuberculous mycobacteria in patients without HIV infection, New York City. Emerg Infect Dis 2008;14:390396. rner H. Incidence and clinical 11. Thomsen VO, Andersen AB, Mio signicance of nontuberculous mycobacteria isolated from clinical specimens during a 2-y nationwide survey. Scand J Infect Dis 2002;34: 648653. 12. Van Ingen J, Bendien SA, de Lange WC, Hoefsloot W, Dekhuijzen PN, Boeree MJ, van Soolingen D. Clinical relevance of non-tuberculous mycobacteria isolated in the Nijmegen-Arnhem region, The Netherlands. Thorax 2009;64:502506. 13. Hoefsloot W, Boeree MJ, Van Ingen J, Bendien S, Magis C, de Lange W, Dekhuijzen PN, van Soolingen D. The rising incidence and clinical relevance of Mycobacterium malmoense: a review of the literature. Int J Tuberc Lung Dis 2008;12:987993. 14. Koh WJ, Lee JH, Kwon YS, Lee KS, Suh GY, Chung MP, Kim H, Kwon OJ. Prevalence of gastroesophageal reux disease in patients with nontuberculous mycobacterial lung disease. Chest 2007;131:18251830. 15. Thomson RM, Armstrong JG, Looke DF. Gastroesophageal reux disease, acid suppression, and Mycobacterium avium complex pulmonary disease. Chest 2007;131:11661172. 16. Bodmer T, Miltner E, Bermudez LE. Mycobacterium avium resists exposure to the acidic conditions of the stomach. FEMS Microbiol Lett 2000;182:4549. 17. Rosenzweig SD, Holland SM. Defects in the interferon-g and interleukin12 pathways. Immunol Rev 2005;203:3847. 18. Winthrop KL, Chang E, Yamashita S, Iademarco MF, LoBue PA. Nontuberculous mycobacterial infections in persons receiving antitumor necrosis factor-a therapy: a review of the FDA adverse event database. Emerg Infect Dis 2009;15:15561561. 19. Winthrop KL, Yamashita S, Beekmann S, Polgreen PM; Emerging Infections Network. Reply to Wallis from Winthrop et al. Clin Infect Dis 2008;47:1606. 20. Van Ingen J, Boeree M, Janssen M, Ullmann E, de Lange W, de Haas P, Dekhuijzen R, van Soolingen D. Pulmonary Mycobacterium szulgai infection and treatment in a patient receiving antitumor necrosis factor therapy. Nat Clin Pract Rheumatol 2007;3:414419. 21. Kwon YS, Kim EJ, Lee SH, Suh GY, Chung MP, Kim H, Kwon OJ, Koh WJ. Decreased cytokine production in patients with nontuberculous mycobacterial lung disease. Lung 2007;185:337341. 22. Jick SS, Lieberman ES, Rahman MU, Rahman MU, Choi HK. Glucocorticoid use, other associated factors, and the risk of tuberculosis. Arthritis Rheum 2006;55:1926. 23. Weycker D, Edelsberg J, Oster G, Tino G. Prevalence and economic burden of bronchiectasis. Clin Pulm Med 2005;12:205209. 24. Prasad M, Tino G. Bronchiectasis. 1. Presentation and diagnosis. J Respir Dis 2007;28:545554. 25. Olivier KN, Weber DJ, Wallace RJ Jr, Faiz AR, Lee JH, Zhang Y, Brown-Elliot BA, Handler A, Wilson RW, Schechter MS, et al.; Nontuberculous Mycobacteria in Cystic Fibrosis Study Group. Nontuberculous mycobacteria: multicenter prevalence study in cystic brosis. Am J Respir Crit Care Med 2003;167:828834. 26. Askamit TR. Mycobacterium avium complex pulmonary disease in patients with pre-existing lung disease. Clin Chest Med 2003;23:643653.
982
VOL 182
2010
27. Oregon Department of Human Services: Acute and communicable disease prevention: tuberculosis (accessed July 2010). Available from http://www.oregon.gov/DHS/ph/acd/arpt/arpt07/tb.pdf 28. Marras TK, Chedore P, Ying AM, Jamieson F. Isolation prevalence of pulmonary non-tuberculous mycobacteria in Ontario, 19972003. Thorax 2007;62:661666. 29. Oregon Department of Human Services: Acute and communicable disease prevention: legionellosis (accessed July 2010). Available from http://www.oregon.gov/DHS/ph/acd/arpt/arpt06/legion.pdf 30. Falkinham JO III, Norton CD, Le Chevallier MW. Factors inuencing numbers of Mycobacterium avium, Mycobacterium intracellulare, and other mycobacteria in drinking water distribution systems. Appl Environ Microbiol 2001;67:12251231.
31. Primm TP, Lucero C, Falkinham JO. Health impacts of environmental mycobacteria. Clin Microbiol Rev 2004;17:98106. 32. Falkinham JO III, Iseman MD, de Haas P, van Soolingen D. Mycobacterium avium in a shower linked to pulmonary disease. J Water Health 2008;6:209213. 33. Von Reyn CF, Arbeit RD, Horsburgh R, Ristola MA, Waddell RD, Tvaroha SM, Samore M, Hirschhorn LR, Lumio J, Lein AD, et al. Sources of disseminated Mycobacterium avium infection in AIDS. J Infect 2002;44:166170. 34. Conger NG, OConnell RJ, Laurel VL, Olivier KN, Graviss EA, Williams-Bouyer N, Zhang Y, Brown-Elliott BA, Wallace RJ Jr. Mycobacterium simae outbreak associated with a hospital water supply. Infect Control Hosp Epidemiol 2004;25:10501055.