Nontuberculous mycobacteria (NTM) represent a diverse group of mycobacterial species; this complex differs from the Mycobacterium tuberculosis complex and Mycobacterium leprae. NTM are ubiquitous environmental bacteria and are mainly present in the natural and drinking water systems, pools and hot tubs, biofilms, and soil [1]. They can affect various tissues and body fluids, causing pulmonary and extrapulmonary diseases [2,3]. Although NTM are considered opportunistic pathogens, the incidence and prevalence rate of NTM pulmonary disease (NTM-PD) are increasing worldwide, not only in the immune-compromised, but also in the immune-competent patients [2-4]. Furthermore, there are significant geographic differences in the distribution of NTM primarily due to the environmental nature of these microorganisms [5].

In South Korea, a country with an intermediate tuberculosis (TB) burden [6], NTM are also emergent pathogens, and NTM-PD is rapidly becoming a significant public health concern. Several studies have reported an increase in both the NTM recovery rate in clinical specimens and the incidence and prevalence rate of NTM-PD in South Korea [7-13]. However, comprehensive analyses of the clinical and epidemiologic data for NTM-PD are relatively scarce compared to that of TB because NTM-PD is not a reportable disease in most countries, and complicated criteria and extensive follow-up are required for diagnosis.

We had previously reported the change in the NTM epidemiology in a tertiary referral hospital in South Korea between 2006 and 2010 [7]. In this study, we aimed to investigate the long-term epidemiologic trends of NTM-PD within the recent 11-year period in a tertiary referral hospital in South Korea. Moreover, we intend to perform comprehensive analyses of NTM-PD and its association with age and sex.

This study found that the incidence rate of NTM-PD continued to increase between 2006 and 2016 in a tertiary hospital in South Korea. Moreover, there were some differences in the clinical characteristics of the patients with NTM-PD according to age, sex, and radiologic forms of the disease.

An increased rate of isolated NTM and NTM-PD has been reported worldwide. In Korea, the incidence rate of NTM continues to increase despite no significant change in the incidence rate of TB (88/100,000 in 2006, and 77/100,000 in 2016) [6,15]. One of the most traditional explanations for this increase is improved detection rates with new laboratory techniques, frequent CT scans during medical check-ups, and increasing awareness of NTM by the medical staff. However, this detection bias may also be partly due to other reasons. In our institution, the increase in the recovery rate was more prominent for NTM than for M. tuberculosis when we used a combination of liquid and solid media for mycobacterial culture, as has previously been reported [16]. However, when we re-analyzed the mycobacterial recovery rate for the solid culture medium, an increasing trend for NTM isolates and patients with NTM-PD was also evident [7]. Therefore, the increase in the detection of NTM isolates and patients with NTM-PD in this study could not be fully explained by the introduction of the liquid culture methods.

We hypothesized that the increase in the incidence rate of NTM-PD was a multifactorial event that includes aging of the general population, an increasing number of patients with comorbidities, and environmental factors. Previous studies have reported that age is related to the increase in the incidence rate of NTM-PD in both young and old populations [17,18]. Al-Houqani et al. [19] reported that age is considered to play the major role in the increase of NTM-PD incidence; however, they also stated that age accounted for less than 25% of the total increase. In the current study, the incidence rate and its increase were more prominent in the old population than in the total population (Fig. 2B). We classified the patients according to age in decades and found an increase in the annual percent change in the incidence rate according to age. Prevots et al. [20] showed similar results; they found a higher increase in the annual prevalence in individuals aged ≥ 60 years than in those aged < 60 years. Adjemian et al. [21] also calculated the adjusted odds ratio of the NTM-PD incidence in different age groups compared to that in patients aged < 18 years, and reported that it is increased according to age: 7.4 (95% CI, 2.9 to 19.3) in patients aged 18 to 49 years; 31.2 (95% CI, 12.2 to 79.7), patients aged 50 to 64 years; and 106.4 (95% CI, 42.0 to 270.0), patients aged ≥ 65 years.

Chronic lung diseases, such as COPD, bronchiectasis, cystic fibrosis, and pneumoconiosis are important predisposing factors for the development of NTM-PD [4]. The underlying structural lung disease and airway dysfunction may intuitively reduce the clearance of the inhaled environmental microorganisms. The prevalence of bronchiectasis markedly increases with age, and NTM infection easily occurs as a comorbidity with bronchiectasis [22]. In the current study, bronchiectasis (83.9%) was the most frequently associated chronic lung disease, followed by previous pulmonary TB (48.3%) and COPD (13.5%). Furthermore, the proportion of the patients with NB form also increased significantly during the study period (Fig. 4 and Supplementary Fig. 1). It is unclear whether NTM-PD is a cause or the consequence of bronchiectasis, but both notions are supported by accumulated evidence [23]. A history of pulmonary TB and other pulmonary infections can be a risk factor for bronchiectasis and structural lung disease. The increased global burden of COPD and use of corticosteroid inhalation could partly explain the increasing trend of NTM-PD incidence [24,25].

We found an increased number of NTM-PD patients and a stable proportion of patients with MAC-PD, which implies that MAC infection is the main reason for the increasing trends in this study. In South Korea, MAC is the most common organism causing NTM-PD [1]. Ko et al. [12] suggested that the proportion of MAC infection, especially of M. avium, has increased over 15 years in Korea . An American study also revealed an increasing trend of MAC infection with relatively stable numbers of all other NTM species over the last 8 years [21].

A few studies have indicated the sex-related differences in the clinical characteristics of NTM-PD. In a French retrospective study, men were younger than women (48.1 years vs. 55.0 years, p = 0.04), and they showed more considerable improvement at 1 year (odds ratio, 2.34; 95% CI, 1.26 to 8.16) [26]. However, the study included a small number of patients (n = 119), and the 1-year mortality rate was higher among men. In a Japanese cross-sectional study that included 11,034 patients with NTM-PD identified from a national database, the incidence rate of NTM-PD was higher among women in all age groups except for those aged ≥ 80 years, which was similar to the results of our study [27]. Holt et al. [28] reported more severe disease in women, evidenced by more cavitation of the lung, lower body mass index, and more extensive treatment history, and a trend towards more marked ventilatory impairment. However, we could not evaluate the severity or treatment history of NTM-PD using our data.

In the current study, women were younger than men, and the peak incidence rate of NTM-PD was in the 50s for women, while that in men was in the 70s. Multi-species NTM-PD was more common in women. Comorbidities were also different; bronchiectasis was more common in women, whereas a higher proportion of men had a history of TB and COPD. This indicates that the reason for increasing NTM-PD incidence rate may differ according to the sex. Nevertheless, the data supporting the sex-related difference hypothesis were limited and equivocal; therefore, prospective studies with a larger cohort are needed.

There are a few limitations of this study. First, the study had a retrospective design. We can only assume the correlation between the disease and clinical characteristics. Second, we analyzed the data from a single center. Although a relatively high numbers of samples and patients were included in the investigation, the clinicodemographic characteristics of the patients visiting our hospital might have affected the result. Third, our institution is a referral hospital frequented by patients with comorbidities. Therefore, the data may not represent the general epidemiology in South Korea due to the referral bias. Fourth, environmental factors for each patient were not considered as part of this retrospective study.

In conclusion, the increased incidence rate of NTM-PD continued from 2006 to 2016 at a tertiary referral hospital in South Korea, possibly owing to the aging of the general population with comorbidities. Furthermore, there might be some age- and sex-related differences in the clinical characteristics. As the incidence rate of NTM-PD is projected to continue to increase, a prospective evaluation to understand the nature of the disease and the inherited and acquired host factors is warranted.