Published ahead of print on May 16, 2007, doi:10.1164/rccm.200702-201OC
© 2007 American Thoracic Society doi: 10.1164/rccm.200702-201OC
Nontuberculous Mycobacterial Sensitization in the United StatesNational Trends over Three Decades1 Department of Medicine, University of Toronto, Toronto, Canada; 2 Centre for Research on Inner City Health, The Keenan Research Centre, Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Canada; 3 Department of Medicine, Division of Respirology, University of Toronto, Toronto, Canada; and 4 Joint Division of Respirology, Department of Medicine, University Health Network and Mount Sinai Hospital, Toronto, Canada Correspondence and requests for reprints should be addressed to T. K. Marras, M.D., M.Sc., Toronto Western Hospital, 7E-452, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8. E-mail: ted.marras{at}utoronto.ca
Rationale: The prevalence of pulmonary nontuberculous mycobacterial (NTM) infections in the United States appears to be rising, but it is unclear if this is due to enhanced detection or actual increases in the burden of infection. Temporal changes in the epidemiology of Mycobacterium intracellulare sensitization may help explain recently observed trends in pulmonary NTM infections. Objectives: Describe the epidemiology of M. intracellulare sensitization in the United States in 1971–1972 and 1999–2000. Methods: We studied nationally representative cohorts of the United States' noninstitutionalized civilian population participating in the 1971–1972 and 1999–2000 National Health and Nutrition Examination Surveys (NHANES). Participants were skin tested with M. intracellulare antigen and sensitization prevalence was compared across NHANES surveys and between participant subgroups. Logistic regression was used to identify associations between participant characteristics, environmental factors, and NTM sensitization. Measurements and Main Results: The 1971–1972 and 1999–2000 NHANES cohorts included 1,490 and 7,384 individuals, respectively. Between 1971–1972 and 1999–2000, the prevalence of M. intracellulare sensitization increased from 11.2% (95% confidence interval, 9.2–13.5%) to 16.6% (95% confidence interval, 13.2–20.6%). On multivariate analysis of the 1999–2000 cohort, age, sex, race, birthplace, education, and occupation were strongly associated with M. intracellulare sensitization. Conclusions: In 1999–2000, an estimated one in six persons in the United States demonstrated M. intracellulare sensitization, up from one in nine persons in 1971–1972. The observed rising prevalence of sensitization is consistent with observed increases in the rates of pulmonary NTM infections in the United States.
Key Words: Mycobacterium infections, atypical • skin testing • epidemiology • trends • risk factors
Nontuberculous mycobacteria are ubiquitous environmental organisms, well known to cause progressive pulmonary disease, skin and soft tissue infections, lymphadenitis, and disseminated disease in immunocompromised people. Although analogous to tuberculosis in some ways, the natural history of infection with nontuberculous mycobacteria is poorly understood and it is unknown if there is a state of latent infection with potential for post-primary activation. Furthermore, the mere presence of nontuberculous mycobacteria in respiratory secretions is not diagnostic of clinically important pulmonary infection. Potentially confusing terms, such as colonization versus disease, or indolent versus advanced infection, have been used to describe this clinical observation. Mycobacterium avium complex (MAC; M. avium and M. intracellulare) is the most common cause of clinically important pulmonary infection with nontuberculous mycobacteria (NTM), with M. intracellulare being the more common respiratory pathogen (1). The prevalence of pulmonary NTM infection varies widely by geographic region and appears to be increasing significantly. Previous population-based studies include reports of 1.5- to 6-fold increases over 5- to 30-year study periods (2). It is uncertain if the observed rise in NTM infections is due to a true increase in the frequency of infection or a surveillance bias from increased awareness and testing, and enhanced microbiologic detection methods (3–7). Microbiologic studies of NTM infection are limited by the possibility of surveillance bias, because they almost never include systematic or random population samples. Microbiologic studies also often lack complete clinical data, preventing a full understanding of the frequency of indolent versus advanced infection. Skin test studies could be used to address common limitations of microbiologic studies. Skin test studies identify people with a delayed-type hypersensitivity reaction to NTM antigen preparations, a surrogate for an exposure or infection that incited a T-cell response, possibly akin to infection with M. tuberculosis complex organisms. Skin test studies lack important microbiologic information regarding the presence or absence of a recoverable infecting organism, but they provide a feasible method of unbiased sampling to assess the frequency of sensitization to NTM antigens and thus NTM exposure or infection. Repeated random population samples could provide an unbiased assessment of temporal changes in the frequency of NTM sensitization, and thus either support or refute findings of microbiologic studies. Although increases in NTM sensitization cannot, per se, prove that there are similar increases in the frequency of clinically important NTM infection, a finding of increasing NTM sensitization may indicate that there is not only a growing population of people who are sensitized but potentially also a growing population at risk of developing clinically important NTM infection. It may stand to reason that, if more people are becoming sensitized, more people could also be developing infection. Increasing prevalence of NTM sensitization might help place recently observed trends in pulmonary NTM infections in context. An increase in sensitization over time would be compatible with observed increases in pulmonary NTM infections and could imply that observed increases are real. Previous skin test studies have often included cohorts selected on the basis of profession (8), entry into military service (9), or educational training program (10), and have generally been limited to a single time period, and therefore lack generalizability and temporal information. To address these limitations, we conducted an analysis of representative cohorts of the United States' population at two points over 30 years to identify the prevalence of M. intracellulare sensitization and to determine how the prevalence of sensitization has changed over time. We also sought to explore associations between selected demographic characteristics, environmental factors, and M. intracellulare sensitization as possible risk factors for pulmonary NTM infection. To connote skin test reactivity, we use the term "sensitization" rather than "infection" for two reasons. First, some authorities on nontuberculous mycobacteria prefer to reserve the term "infection" for advanced nontuberculous mycobacterium–related disease that, by definition, includes symptoms and radiographic signs. Second, unlike the case with tuberculosis, there is as of yet an incomplete understanding of the pathogenesis and natural history of NTM infection and its association with skin test reactivity.
Survey Design and Data Collection The National Health and Nutrition Examination Survey (NHANES) is conducted periodically by the National Center for Health Statistics, Centers for Disease Control and Prevention (CDC), to obtain statistics on the health and nutritional status of the United States population. This objective is accomplished by conducting household interviews, performing standardized physical examinations, and collecting and testing biological specimens from participants from randomly selected locations across the country. When sample weights are applied, the distribution of participants in NHANES approximates that of the noninstitutionalized civilian population of the United States as a whole. In this analysis, NHANES data from two public use files were analyzed (1971–1972 and 1999–2000), each of which was based on a complex, stratified, multistage, probability-sample design. Data from NHANES 1999–2000 included information on participant characteristics (e.g., age, sex, race/ethnicity, birthplace, education, income, occupation, smoking status, prior lifetime contact with active tuberculosis, presence of a scar from bacille Calmette-Guérin [BCG] vaccination on examination) as well as environmental factors (e.g., dwelling type, water source, use of home water treatment devices). Data collected from NHANES 1971–1972 were used for comparative purposes (i.e., with NHANES 1999–2000). A total of 9,965 individuals aged 1 year or older participated in NHANES 1999–2000, of which 7,384 (74.1% of total) were skin tested with M. intracellulare antigen (purified protein derivative [PPD]-B) and M. tuberculosis–derived tuberculin (PPD-S). In NHANES 1971–1972, skin testing was restricted to a subgroup of 1,490 participants between the ages of 25 and 74 years.
Skin Testing
Statistical Analysis Backward elimination logistic regression in SUDAAN was used to identify independent predictors of NTM sensitization among all participants (i.e., 1+ yr) and adults (20+ yr) in the 1999–2000 NHANES cohort. Variables significant at the p < 0.10 level were allowed to remain in the final multivariate model. This investigation was approved by the St. Michael's Hospital Research Ethics Board.
Sensitization to M. intracellulare is common in the United States, with about one in six (16.6%; 95% confidence interval [CI], 13.2–20.6%) persons in 1999–2000 demonstrating skin test positivity (see Table 1). Among the noninstitutionalized civilian population of the United States, this translates into approximately 37.8 million sensitized people. Our analysis also demonstrates a significant age effect, with the highest prevalence of sensitization noted among persons in the 20- to 39-year age group (20.6%; 95% CI, 15.6–26.7%). Men had a higher prevalence of sensitization (19.2%; 95% CI, 15.3–23.7%) than women (14.1%; 95% CI, 10.9–18.0%), whereas non-Hispanic blacks (31.5%; 95% CI, 24.1–40.1%) had the highest prevalence of sensitization among different racial/ethnic groups. Foreign-born persons from Mexico (23.3%; 95% CI, 18.6–28.8%) or other parts of the world (24.5%; 95% CI, 19.3–30.6%) also displayed a higher prevalence of sensitization than persons born in the United States (15.3%; 95% CI, 11.9–19.3%). A higher prevalence of sensitization was also observed among persons residing in apartments or other homes not classified as a "house" (19.7%; 95% CI, 14.3–26.6%), in those residing in households not using water treatment devices (18.1%; 95% CI, 14.5–22.4%), and in persons with BCG scars noted on examination (23.0%; 95% CI, 16.8–30.7%). Age standardization did not influence the significance of these observations.
Among adults 20 years of age or older, having less than a high school education (24.9%; 95% CI, 21.0–29.4%), current smoking (22.6%; 95% CI, 18.2–27.6%), and occupation (current or longest held) in an agricultural or construction-related field (26.3%; 95% CI, 20.7–32.8%) were each associated with a higher prevalence of sensitization. Factors not significantly associated with sensitization included poverty status, household water source, and prior lifetime contact with active tuberculosis. Parallel findings were observed on univariate logistic regression analysis (see Table 2).
On multivariate analysis of all study participants (age  1 yr), factors significantly associated with an elevated risk of sensitization included age (greatest odds among persons age 20–39), male sex, race/ethnicity (greatest odds among non-Hispanic blacks, lowest odds among Mexican Americans), and birthplace outside the United States (greatest odds among persons born in Mexico) (see Table 3). On multivariate analysis of adults 20 years and older (see Table 3), factors associated with an elevated risk of sensitization included age (lowest odds among persons > 60 yr), male sex, race/ethnicity (greatest odds among non-Hispanic blacks, lowest odds among Mexican Americans), birthplace outside the United States (greatest odds among persons born in Mexico), education (greatest odds among those with less than a high school education), and occupation (current or longest held) in an agricultural or construction-related field. Smoking status approached but did not achieve statistical significance in the final multivariate model (p = 0.09), with current smokers demonstrating the greatest odds of sensitization.
Our data also demonstrate an upward trend in M. intracellulare sensitization (see Figure 1). In 1971–1972, the prevalence of sensitization was estimated at 11.2% (95% CI, 9.2–13.5%), whereas in 1999–2000, the prevalence had risen to 16.6% (95% CI, 13.2–20.6%). Among the United States–born population (aged 25–74 yr), the age-standardized prevalence of sensitization increased from 10.9% (95% CI, 8.8– 13.4%) to 16.2% (95% CI, 12.9–20.1%), representing a 49% increase. Among the nation's foreign-born population (aged 25–74 yr), age-standardized sensitization increased by an even greater extent, from 11.7% (95% CI, 6.8–19.4%) to 26.7% (95% CI, 21.9–32.2%), representing a 128% increase.
Our study reveals a clear increase in the prevalence of NTM sensitization in the United States during the past three decades. These findings are consistent with the increased prevalence of pulmonary M. intracellulare/MAC infection that has been described in previous studies. Yet, the biologic relationship between sensitization and clinical infection with M. intracellulare remains unclear (1). It may be that there is a latent state, or that people are being exposed and developing an immune response to M. intracellulare, and possibly other nontuberculous mycobacteria repeatedly. American Thoracic Society guidelines seem to support the notion of an asymptomatic infection, by stating that "skin test studies in adults indicate that a substantial proportion have had prior and presumably asymptomatic infection with NTM"(1). We assume that exposure (and usually immunologic sensitization) is necessary but not sufficient in the pathogenesis of clinically apparent NTM infection. In addition to supporting microbiologic studies reporting rising rates of pulmonary NTM infections, our study also provides an important benchmark to which future epidemiologic studies can be compared. The high prevalence of M. intracellulare sensitization that we observed is difficult to compare with earlier skin test studies due to significant differences in study methods and design. In a landmark study of over 20,000 nursing students in the United States from 1943–1949, sensitization to nontuberculous mycobacteria was defined as less than 5 mm of induration to an initial 5–tuberculin unit (TU) PPD-S skin test and at least 5 mm of induration to a subsequent 250-TU PPD-S skin test (10). The authors reasoned that a reaction to only the high dose indicated nonspecific mycobacterial sensitization due to nontuberculous mycobacteria. The presumed nonspecificity among mycobacterial species, and the possibility of booster reactions, suggests that the observed 34% sensitization rate cannot be compared with our results. In another seminal study, PPD-B skin tests were administered to greater than 275,000 U.S. naval recruits from 1958–1965 (9). The definition of sensitization to PPD-B was at least 4 mm of induration, differing considerably from a current definition of sensitization (induration to PPD-B of at least 5 mm and at least 3 mm greater than the reaction to PPD-S). Thus, the observed sensitization rate of 29% is also difficult to compare with our findings. Since the definitions used in both the previously noted studies are nonspecific, the high rates of sensitivity they observed are not unexpected. In more recent work, 484 healthy subjects from a number of sites around the world were studied, and M. avium–dominant reactions (at least 5 mm induration to M. avium sensitin and at least 3 mm greater than the reaction to PPD-S, as in our study) were identified in 12% (24/206) of those tested in the two locations in the United States (13), slightly lower than our national estimate of 16.6% (95% CI, 13.2–20.6%). Data limitations prevented conclusions regarding either the national prevalence of NTM sensitization or an assessment of temporal trends. In a recent study, the prevalence of sensitization to M. avium was assessed in a geographic area believed to have high rates of NTM infection, Western Palm Beach, Florida (14). In this study, a random sample of local residents was skin tested, with a positive test defined as at least 5 mm induration to M. avium sensitin and a reaction that was at least 3 mm greater than the reaction to PPD-S. Thirty-three percent of the 447 participants had positive tests, consistent with the impression that the southeastern United States has particularly high rates of NTM infection (9, 10). Possibly of greater importance than the absolute frequency of sensitization in our study was the substantial increase in the prevalence over time among the age groups studied in each of the two NHANES surveys (i.e., ages 25–74). The difference between the national estimate of 11.2% in the 1971–1972 cohort and 16.6% in the 1999–2000 cohort represents a nearly 50% increase during the past three decades. This increase is consistent with the rising rates of pulmonary M. intracellulare/MAC infections that have been observed in microbiologic studies (2–7), but, to our knowledge, rising rates have not previously been demonstrated in skin test studies. Our findings, in conjunction with consistent reports from microbiologic studies, creates a compelling argument that M. intracellulare/MAC infection rates are truly increasing, and opposes the notion that observed increases are simply due to detection bias. Actual changes in the frequency of NTM infection over time could be due to host changes, pathogen changes, or changes in the interaction between host and pathogen. First, changes in host immunity may be relevant, especially if infections with the M. tuberculosis complex species (15, 16) and BCG (17, 18) provide cross-immunity and protect against infection with nontuberculous mycobacteria. If infections with "protective" mycobacteria decrease, lower levels of cross-immunity may lead to higher rates of NTM infection. In support of this theory, decreasing rates of tuberculosis concomitant with increases in NTM infection have generally been observed (15, 16). Moreover, studies from the Czech Republic (17) and Sweden (18) have reported that children who were not vaccinated with BCG had a far higher rate of extrapulmonary NTM infection, again consistent with the notion that cross-immunity confers some protection across mycobacterial species. Second, pathogen changes over time, such as enhanced virulence, may also contribute to increased rates of NTM infection. NTM isolates from patients have been shown to vary widely in virulence (19), and examples of genetically identified virulence factors include a conserved coding sequence of a macrophage-induced gene (20) and the presence of numerous or large plasmids (21). Third, altered interactions between host and pathogen could include an increase in host exposure to the pathogen due to the transition from predominant tub-bathing to showering (22), a habit that could greatly increase respiratory exposure to water-borne organisms through aerosolization. The difference in sensitization prevalence by place of birth (i.e., foreign- vs. United States–born) across each of the two surveys merits discussion. We observed no significant difference in the age-adjusted prevalence of M. intracellulare sensitization between foreign- and United States–born persons in 1971–1972, but noted a significantly higher age-adjusted prevalence of sensitization among foreign-born persons in 1999–2000. Among foreign-born persons (aged 25–74 yr), sensitization increased from 11.7% in 1971–1972 to 26.7% in 1999–2000, whereas the increase among United States–born persons (aged 25–74 yr) was less prominent (10.9% in 1971–1972 to 16.2% in 1999–2000). The observed rise in M. intracellulare sensitization among foreign-born persons could be the result of changes in immigration patterns. If immigrants to the United States came predominantly from Europe in the 1970s (where the prevalence of NTM exposure may be comparable to the United States), and if recent immigrant groups more often came from Asia, Africa, and Latin America (where a more agrarian-focused lifestyle may increase exposure to NTM), we may be measuring the result of greater environmental contact with M. intracellulare. Unfortunately, data limitations prevented us from further exploring these issues. Our analysis of the 1999–2000 cohort revealed a far higher prevalence of sensitization among foreign-born persons of all ages, 24.2% (95% CI, 19.9–29.2%), compared with United States–born subjects, 15.3% (95% CI, 11.9–19.3%). Dividing the foreign-born cohort into Mexican and non–Mexican-born subjects did not alter this observation. On multivariate analysis, we also found birth outside the United States to be strongly associated with NTM sensitization. One theory that might explain the higher prevalence of sensitization observed in foreign-born persons is that prior M. tuberculosis infection or BCG vaccination could result in false-positive PPD-B skin tests. However, our results do not support this theory, because we did not find an association between prior household contact with active tuberculosis and sensitization to M. intracellulare in the 1999–2000 cohort. Furthermore, we did not observe a significant difference in sensitization prevalence between foreign-born persons with a BCG scar (27.0%; 95% CI, 18.3–37.9%) versus those without a BCG scar (23.3%; 95% CI, 19.2–27.9%). Thus, we presume that the high prevalence of M. intracellulare sensitization observed in the nation's foreign-born population in 1999–2000 is an accurate finding and is not due to cross-reactivity from exposure to other mycobacteria. The reasons for higher M. intracellulare sensitization in foreign-born individuals are not known. Higher rates of tuberculosis and secondary bronchiectasis or bronchiolectasis in foreign-born residents of the United States could predispose to infection with less pathogenic organisms, like M. intracellulare. In addition, foreign-born subjects may have greater exposure to environmental mycobacteria, like M. intracellulare, if they originate from a tropical region and have higher rates of soil exposure in agriculture (14). Results in the 1999–2000 cohort are consistent with very high rates of pulmonary NTM isolation observed in two South African studies, wherein random samples of people in the Natal and Transkei regions recovered nontuberculous mycobacteria from 17 of 1,196 (infection rate, 1,400/100,000) (23) and 150 of 2,230 (infection rate, 6,700/100,000) (24) subjects' sputum, respectively, rates nearly two orders of magnitude greater than those in North American and European microbiologic studies.
Our study also contributes important information regarding risk factors for NTM sensitization. Male sex, non-Hispanic black race, and birth outside the United States were each independently associated with M. intracellulare sensitization. Our results support the validity of a recent study in which similar associations were observed, despite the exclusion of people with indeterminate skin test results (PPD-B In our study, age was strongly associated with sensitization, with the highest prevalence in the 20- 39-year age group, followed by successively decreasing prevalence in the 40 to 59, and 60 years and older age groups, respectively. The finding that the 20- to 39-year-old cohort had the highest prevalence of sensitization could reflect either an intrinsic susceptibility at this age or confounders of lifestyle (e.g., showering) or occupational (e.g., agricultural or construction work) exposures that are more prevalent in this age group. In a recent study, sensitization prevalence peaked in the 41- to 50-year age group, possibly reflecting different characteristics of their cohort, the fact that they excluded people with indeterminate results from their risk factor analysis, or the smaller sample size, leading to less precise estimates, possibly sensitive to small peculiarities of their sample (14). The consistent finding of less frequent sensitization in people older than 60 years is puzzling. Our large population-based sample suggests that the peak in sensitization occurs in people aged 20 to 39 years, but pulmonary NTM infection is generally considered a disease that is most common in the elderly (1). It is impossible to explain this observation based on our data alone, but we speculate that it could be related to waning of the immune system with age. It may be that there is very frequent exposure to M. intracellulare from a young age, and the resulting sensitization is a marker only of immune-system recognition of this organism, regardless of the existence of a latent state of infection. In youth, the exposure may not lead to clinically important infection due to a relatively robust immune system. As people age, a general waning of immune-system function could explain both the lower frequency of sensitization (an inability to mount a delayed-type hypersensitivity response to an organism that has previously been recognized) and the higher frequency of clinically important infection (due to an inability to contain an organism that newly enters, or previously survived within, the lungs). On multivariate analysis, we did not find a statistically significant association between sensitization and either the source of household water (i.e., regional water distribution facility vs. well water) or whether people were using water treatment devices in their home. It is interesting to note, however, that on univariate analysis, people whose water originated from a public or private water company had a slightly higher odds of M. intracellulare sensitization (odds ratio, 1.41; 95% CI, 0.88–2.25), whereas people using water treatment devices in the home had a slightly lower prevalence of sensitization (odds ratio, 0.64; 95% CI, 0.41–1.00). Data limitations on water sources and treatment devices, however, precluded us from conducting a more rigorous evaluation of this interesting association. Finally, our observation that active smoking is associated with increased odds of M. intracellulare sensitization is an intriguing new finding. This association appears to be consistent with the common clinical observation that an extensive smoking history and emphysema are common risk factors for advanced pulmonary NTM infection (1) and appears to be consistent with the association between smoking and tuberculosis infection (25). Our study has several important limitations. Foremost, the design is cross-sectional, limiting our ability to make causal inferences about relationships between risk factors and M. intracellulare sensitization. Our study was also limited by the nature of data collected in NHANES surveys; however, we believe this analysis represents an important epidemiologic benchmark in studying nontuberculous mycobacteria, given that it includes data on a nationally representative cohort of the noninstitutionalized civilian population of the United States and examines temporal changes from three decades earlier. Our ability to evaluate changes in the prevalence of sensitization over time, however, was limited by the size and characteristics of the cohorts studied and the methods used across each of the two NHANES surveys. For example, the 1971–1972 survey restricted skin testing to persons aged 25 to 74 years and included only 1,490 individuals, thereby restricting temporal comparisons to this age range and reducing power to detect differences between important subgroups. Along these lines, variables across the two surveys were not always defined identically. For example, the definition of race in the 1971–1972 survey was substantially different from the definition used in 1999–2000. In this analysis, we restricted subgroup analysis across surveys to comparisons of M. intracellulare sensitization by birthplace. We used the most widely accepted definition for sensitization to nontuberculous mycobacteria, which incorporated the results of both tuberculin and NTM antigen skin tests. It is possible, however, that our definition of sensitization may not precisely capture M. intracellulare exposure, or differentiate NTM exposure from those exposures to other mycobacterial species (e.g., M. tuberculosis, BCG vaccination). Although the use of a single-species antigen for skin testing limits the ability to generalize to other NTM organisms, the selection of M. intracellulare is most appropriate, because MAC is the most common cause of pulmonary NTM syndromes, and M. intracellulare is the more important pulmonary pathogen of this complex (1). In summary, we observed a high prevalence of sensitization to M. intracellulare among a nationally representative sample of the noninstitutionalized civilian population of the United States in 1999–2000, suggesting that NTM infections may be a highly prevalent health problem. More importantly, we observed a substantial increase in the prevalence of sensitization over the past three decades, which corroborates findings from microbiologic studies, and suggests that rising rates of NTM infections are not an artifact of enhanced surveillance or diagnostics.
Supported by the University of Toronto, and in part by the Ontario Ministry of Health and Long Term Care, and Genome Canada through the Ontario Genomics Institute. Originally Published in Press as DOI: 10.1164/rccm.200702-201OC on May 16, 2007 Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form February 6, 2007; accepted in final form May 15, 2007
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