Recovery Rates of Non-Tuberculous Mycobacteria from Clinical Specimens Are Increasing in Korean Tertiary-Care Hospitals

Non-tuberculous mycobacteria (NTM) are a diverse group of species that are widespread in the environment. In addition to the Mycobacterium tuberculosis complex and M. leprae, more than 140 NTM species have been identified (1). Although the majority of NTM species are considered to be only opportunistic pathogens, some can cause pulmonary and extrapulmonary diseases, such as lymphadenitis, skin and soft tissue infections, and disseminated infections, even in immunocompetent hosts (2). Thus, NTM are now recognized as an increasingly important cause of lung disease in various parts of the world (3, 4).

Clinical NTM isolates show geographic and environmental variability, making them potential environmental health concerns (5, 6). In Korea, the NTM isolation rate has increased steadily (7). In late 2000, liquid culture methods were introduced in Korea to improve the sensitivity of laboratory diagnoses. However, studies of NTM-associated disease are still insufficient, especially with respect to extrapulmonary infections. To better understand the current epidemiologic trend of NTM-associated diseases, we studied the frequency of isolation and the species distribution of NTM recovered from various clinical specimens over a 7-year period at 2 Korean tertiary-care hospitals.

We found that the annual proportion of NTM recovered from clinical specimens and the prevalence of NTM-associated lung disease increased significantly between 2009 and 2015, similar to previous reports from Korea. Lee et al. (10) reported that the annual percentage of NTM isolations had increased steadily and that the proportion of patients from whom NTM were isolated increased from 21.4% (2006) to 55.0% (2010). Similarly, Koh et al. (11) reported that the proportion of NTM, among all positive mycobacterial respiratory specimen cultures, increased from 43% in 2001 to 70% in 2011. Further, Park et al. (12) reported that the proportion of NTM among positive mycobacterial cultures increased from 22.2% in 2002 to 45.9% in 2008.

Despite the increasing tendency of NTM-associated disease in our study, there was no significant change in the most commonly isolated species. These species were M. avium and M. intracellulare, followed by M. abscessus, similar to other reports from Korea (12). The prevalence of particular mycobacterial species that are responsible for different diseases differs markedly by geographic region. For example, in the United States and Japan, M. avium, M. intracellulare, and M. kansasii are the most common disease-associated species (1, 13), whereas in England and Scotland, M. kansasii and M. malmoense, respectively, are the most common (14).

In our study, the most common NTM species isolated from extrapulmonary specimens was M. avium (25.0%). M. intracellulare is the most common species isolated from localized pulmonary infections. M. abscessus was commonly found in skin and soft tissue infections, consistent with findings from Taiwan (15). However, among the extrapulmonary isolates, M. abscessus comprised 8.3% of the total, representing only a 0.9% higher proportion of extrapulmonary isolates than of pulmonary specimens.

Identification of clinical isolates to the species level is crucial because the pathogenic potential (virulence) differs among species. The various species also differ in the clinical spectrum of disease they cause, as well as in their susceptibility to antimicrobial drugs. M. kansasii, M. avium, M. intracellulare, M. abscessus, and M. massiliense show relatively high pathogenic potential, whereas M. fortuitum does not. M. gordonae is one of the least pathogenic NTM, and its isolation from the respiratory tract is typically considered to represent contamination rather than infection (16). This means that when NTM are isolated from clinical specimen, species identification is as important as the fact that an NTM was isolated. However, during our study period, the species was identified in only 19.2% of NTM-positive cultures. Given the current ‘fee-for-service’ rule in our healthcare insurance reimbursement system, the identification of NTM to the species level can be performed only at the request of the clinician with the consent of patient. Although in cases where NTM was designated the cause of clinically significant infections requiring medical intervention, the species were not always identified. This tendency was particularly pronounced in the extrapulmonary specimens, particularly when NTM was detected in skin and soft tissue infection-positive specimens from 24 patients. When NTM is detected in skin and soft tissue infections, many surgeons administer empiric antibiotics when their patients have positive mycobacterial cultures, without a request for identification of isolates or antimicrobial susceptibility tests. However, the need for identification to the species level is increasing to guide precise diagnosis and treatment. Therefore, it is necessary to identify the species in every case when NTM is isolated in the mycobacterial culture. In addition, this low rate of requests for identification of NTM to the species level suggests that clinicians do not consider NTM to be important pathogens. These organisms are widely distributed in the environment, including in soil and water (17). Therefore, the isolation of NTM from respiratory specimens does not imply that the patient has an NTM-associated disease. When NTM are isolated from clinical specimens, the percentage of patients with clinically significant NTM-associated disease seems to differ according to the diagnostic criteria used and the global region. In America and European countries, 40%–50% of culture-positive patients are found to have NTM-associated disease (12, 18), whereas only 30%–40% of culture-positive patients in Korea have confirmed NTM-associated disease.

The number of patients with newly diagnosed NTM-associated lung disease also increased steadily during our study period. Several explanations can be offered. The most popular ones are improved laboratory techniques and the increased proportion of the population at risk for such disease (19). The laboratory techniques probably enhance the sensitivity of mycobacterial recovery. For example, the introduction of liquid culture methods enabled us to detect both M. tuberculosis and NTM with greater sensitivity than did the solid-medium method. Although we did not compare the results of solid and liquid culture methods, Lee et al. (10) reported that NTM positivity was significantly higher for liquid culture methods. Globally, the increasing number of individuals with immunodeficiencies, chronic debilitating conditions, and advanced age are contributing to the growing awareness of the pathogenic importance of NTM. Thus, the growing number of patients with NTM infections over the course of our study might be attributable to better diagnosis and to the growing at-risk population.

A variety of clinical information is required to confirm that NTM have caused a significant infection. Since the applicable clinical diagnosis criteria were established in 2007, healthcare utilization and computed tomography imaging of the chest have increased. These increases may also contribute to the more frequent diagnosis of NTM-related lung disease.

The limitations of this study are that only 19.2% of all NTM strains were identified to the species level. The results therefore should be interpreted with caution, as they may not reflect the overall distribution of NTM species accurately. Because this study was retrospective, we could not evaluate all the specimens in which the NTM species were not identified. The reason only a small portion of the isolates were sent for species identification was that all medical activities are fee-for-service, and identification is requested only when patients revisited and agreed to pay for the service. This system resulted in late diagnosis and underestimated the significance of NTM diseases. Kim et al. (20) pointed out these problems and suggested a solution for our health insurance reimbursement system services. But the system has not changed.

In conclusion, we found that the annual percentage of NTM recovered from clinical specimens and the prevalence of patients with NTM infections both increased significantly from 2009 to 2015. The proportion of NTM isolates also has been rising steadily, accounting for 44.8% of all mycobacteria recovered in 2015 at the 2 study hospitals. Further, the number of clinically significant diseases caused by NTM is rising. The most frequently isolated species were M. intracellulare and M. avium.