This first population-based estimate of trends in NTM pulmonary disease in the United States using current ATS microbiologic criteria demonstrates an overall increasing prevalence of pulmonary NTM. The burden estimated here is similar to other recently published estimates, and has increased since the last estimates were published 20 years ago (5
). This analysis also identified infrequent microbiologic sampling for this condition, likely leading to an underestimate of the true burden. In addition, treatment for this condition was infrequent. Comorbid conditions were very similar for persons with a single pulmonary isolate compared with those who met ATS microbiologic criteria; the frequency of underlying conditions was similar to that described previously (1
), with the additional identification of rare conditions associated with this disease.
The only prior population-based study of NTM trends in the United States, conducted in Massachusetts during 1972–1983, identified an increase in disease prevalence (10
). Our trends in this analysis are consistent with those for Ontario, Canada, 1997–2003 (11
), which reflected an annual percent increase in isolation prevalence of 8.4% per year, from 9.4 per 100,000 to 14.1 per 100,000. Only approximately 33% of persons with isolates met ATS microbiologic criteria, corresponding to an estimated increase in disease prevalence in Ontario from 3.1 to 4.6 per 100,000 during that time. At our two West coast sites combined, we found an average annual increase from 1994–1996 to 2004–2006 of 4.5 to 7.5 per 100,000 among women and 3.5 to 4.9 among men. Our population-based data from these large United States health care systems confirm prior clinic-based reports identifying an increase in the numbers of patients with pulmonary NTM disease (1
The reasons for the increasing prevalence likely reflect a combination of increased awareness and detection and true increases in disease. More rapid and specific diagnostics developed over the last 20 years (12
) have increased the ease and capability for identification of mycobacterial species, leading to greater specificity in disease diagnosis. In addition, the recognition of pulmonary NTM among women aged greater than or equal to 60 years with no known underlying risk factors (2
) has led to increasing awareness among physicians, patients, and advocacy groups. The increased use of CT scans also may have facilitated increased diagnosis. Data from serial assessment of skin test sensitization to M. intracellulare
suggest an increasing prevalence of exposure (13
). However, the link between sensitization and overt disease is still unclear. The increasing chlorination of the water supply has been hypothesized to select for NTM over other bacteria, potentially increasing their concentration and the potential for exposure (14
Our overall age-adjusted average annual prevalence of 5.4 per 100,000 for 2004–2006 is higher than the last published estimates of 1.8 per 100,000 in 1984 (5
) and is consistent with a recently published report from a single state, Oregon (15
). The overall prevalence of 4.4 per 100,000 among men and 6.5 per 100,000 among women is nearly identical with that of 4.7 per 100,000 among men and 6.4 per 100,000 among women found in Oregon. The only other current estimate is from one area of Northern Manhattan, which estimated an annual prevalence of pulmonary NTM of 2 per 100,000 for the period 2000–2003 (16
). Because the IHDS studied did not include populations from the Southeastern United States, which have been found to have higher prevalence of NTM isolation and of disease (17
) and also have a high population density, the overall prevalence found here could represent an underestimate of the prevalence for the United States as a whole. However, given the unavailability of comparable disease prevalence estimate from other regions of the United States, we cannot evaluate the degree of this bias with any certainty. With respect to individual level factors, the IHDS studied have a relatively similar age and sex distribution relative to the underlying population in the coverage area, with a slight overrepresentation of persons aged greater than 60 years at KPCO (20% vs. 12% in coverage area). In the one IHDS where this has been systematically assessed (KPSC), the poorest, nonworking population was least likely to be enrolled, which would explain the lower rates of TB in the IHDS population, with an underrepresentation of the lowest (<$35,000/yr) and highest (>$75,000/yr) income groups (D. Strickland, personal communication).
The cases identified in our study more likely represent incident than prevalent cases: greater than or equal to 80% of cases were cases in only a single year, even over a 13- to 16-year period, most likely because they were not routinely cultured for NTM. Persons may not be routinely cultured because their disease is mild and slowly progressing, a lack of awareness by physicians or patients about this condition, or because of a decision not to treat the infection (3
). In a recent large study at a tertiary referral center, patients went an average of 5 years between onset of symptoms and diagnosis (19
). Rates of mycobacterial clearance are low and relapse or reinfection rates are high (20
), contributing to the chronic nature of this condition. For these reasons, our observed prevalence estimates likely underestimate true prevalence. Therefore, to obtain a more complete estimate of the true burden of disease, we estimated cumulative incidence by assuming that once a person was diagnosed and “counted” as a case for our analysis, they would be counted for all subsequent years. Using this approach, the estimated overall age-adjusted cumulative incidence was 2.5-fold greater than the average annual prevalence among men and 3.5-fold greater than that for women. However, this approach does not consider cure rates; some proportion of patients may clear their infection. Therefore, true prevalence may be intermediate between the observed prevalence and that estimated by the cumulative incidence approach.
The geographic differences in estimated prevalence in our study support prior findings showing geographic variability (17
). In 1999, the Centers for Disease Control and Prevention published estimates of isolate prevalence based on patient isolates referred to the state laboratories, demonstrating marked geographic variability; the highest rates were in the Southeastern United States (17
). A study of NTM-associated hospitalizations also found geographic differences in the prevalence of NTM-associated hospitalizations and prevalence trends, with the highest rates in the Southeastern United States (18
). We found the lowest estimates of 1–2 per 100,000 from the site in the Rocky Mountain Region and the highest of 5.2 (men) to 8.1 (women) in Southern California. On the West coast, where the most beneficiaries were observed for the longest time, the prevalence was very similar at the two participating sites, and quite similar to the rates reported from Oregon (15
Treatment for pulmonary NTM disease is lengthy and complex. For the most common mycobacteria, MAC, the ATS has recommended treatment with a multidrug regimen to achieve persistently negative sputum cultures for 12 months; sputum conversion should be observed within 3–6 months (3
). Some patients may meet diagnostic criteria but do not have progressive or severe disease and therefore may be closely monitored with regular sputum collection (3
). We found a low proportion of antibiotic treatment of at least 3 months duration, a minimum estimate of treatment. Physicians may have chosen a “wait and see” approach before prescribing antibiotics. This approach is partially justified by the fact that the reported efficacy of treatment is low. In a recent review of 12 clinical trials with regimens containing macrolides, the median reported efficacy was 56% with a range from 26–71%; the median sample size in these studies was 43 (range, 10–103) (20
). In a recently published large clinical trial, the proportion of patients with M. avium
infection treated with a currently recommended regimen who were alive and reported “cured” at 5 years was 31% (21
). Drug intolerance and dose-dependent toxicity are common, particularly in the elderly: from 10–50% of patients experience side effects of varying severity to the commonly prescribed drugs for MAC disease (3
). Therefore, for many patients and their physicians, even when the disease is recognized, the perceived benefit of treatment is low.
The frequency of underlying conditions was similar to that described previously, and was similar between possible and definite cases. Approximately a third of cases had COPD, commonly associated with NTM (1
). The frequency of bronchiectasis was also high. The higher frequency of bronchiectasis among women than men is consistent with the greater proportion of women without other known underlying risk factors (1
). Less than half of all cases were coded as having pulmonary NTM; because NTM is a relatively rare and often unrecognized condition, the codes may not be listed on standard discharge or billing sheets and physicians or coders may not be as likely to assign this code. The higher proportion of definite cases coded as NTM among women (31%) compared with men (20%) suggests that NTM in men may be considered as incidental to their underlying condition (and therefore not coded), whereas among women without other underlying risk factors NTM is considered primary.
Underlying and associated conditions were quite similar among possible cases (persons with only a single positive sputum sample) compared with definite cases (persons with two positive sputum samples, or a positive culture from bronchoalveolar lavage or lung biopsy). The radiographic findings in these two groups were also quite similar, which could be explained in part by the similar frequency of underlying conditions, such as malignancies and COPD, or by a similar frequency of NTM disease in both groups. Both groups had a similar number of specimens collected: overall, on average, 3.4 samples per possible case, and 4.8 samples per definite case. These data suggest that the current ATS criteria, which recommend the collection of three sputum samples for diagnosis, and the use of two positive sputum samples rather than a single positive sputum culture to establish the diagnosis of disease, may differentiate poorly between those who do not have disease and those who have milder indolent disease that may progress to a more severe disease state. Although the ATS recommends follow-up with regular collection of sputum samples for patients with a single sputum sample, in this study the low average number of samples over a long time period indicates that most patients were not receiving standard recommended follow-up cultures. Approximately one fifth of definite cases had been possible cases in another year. In the absence of routine sputum cultures, a single positive sputum sample may be sufficient evidence of disease if radiographic findings and clinical features are consistent with disease.
Evaluation of our case definition is limited. One recent study in Denmark evaluated a small subset of patients who met ATS microbiologic criteria: 90% of those who met microbiologic criteria and were classified as “possible cases” in our study met additional radiographic and clinical criteria. Thus, by using microbiologic criteria alone, we may slightly overestimate disease prevalence. In addition, the use of this definition may underestimate the proportion of disease from organisms with a relatively high pathogenicity, such as M. kansasii
The increasing prevalence of pulmonary NTM disease and declining rates of TB represent the new epidemiology of mycobacterial disease in the United States. The incidence of TB in the United States declined to 3.8 cases per 100,000 population in 2009, for a decrease of 11.4% from 2008, continuing a progressive decline since the 1990s (24
). NTM seems to have surpassed TB as the leading cause of mycobacterial lung disease in the United States.