A narrative review of nontuberculous mycobacterial pulmonary disease: microbiology, epidemiology, diagnosis, and management challenges

ABSTRACT

Introduction

Nontuberculous mycobacteria (NTM) are a diverse group of mycobacterial species that are ubiquitous in the environment. They are opportunistic pathogens that can cause a range of diseases, especially in individuals with underlying structural lung disease or compromised immune systems.

Areas covered

This paper provides an in-depth analysis of NTM infections, including microbiology, environmental sources and transmission pathways, risk factors for disease, epidemiology, clinical manifestations and diagnostic approaches, guideline-based treatment recommendations, drugs under development, and management challenges.

Expert opinion

Future approaches to the management of NTM pulmonary disease will require therapies that are well tolerated, can be taken for a shorter time period and perhaps less frequently, have few drug–drug interactions, and are active against the various strains of pathogens. As the numbers of infections increase, such therapies will be welcomed by clinicians and patients.

KEYWORDS:

• Nontuberculous mycobacteria
• pulmonary disease
• epidemiology
• antibiotic resistance
• diagnostics
• Mycobacterium avium complex
• Mycobacterium abscessus complex

1. Introduction

Mycobacteria are a group of aerobic organisms known for their acid-fastness and thick, lipid-rich cell walls [1]. They are considered one of the oldest bacterial genera, with evidence of their existence dating back millions of years [2]. The most well-known mycobacterial species is Mycobacterium tuberculosis, the causative agent of tuberculosis (TB) that primarily affects the lungs and spreads from person to person through the inhalation of respiratory droplets [3]. While TB has been decreasing around the world, there has been a simultaneous increase in disease caused by nontuberculous mycobacteria (NTM) [4], a diverse group of organisms that are ubiquitous in the environment [5]. With the exception of M. tuberculosis complex, Mycobacterium leprae complex, and Mycobacterium ulcerans, the rest of the species are referred to as NTM [6]. NTM pulmonary disease (NTM-PD) accounts for the majority of NTM-associated diseases, which include lymphadenitis, skin and soft tissue infections, cardiac infection, bone and joint infections, and disseminated disease [7–9].

We conducted a narrative review of the literature to outline the microbiology, environmental sources and transmission pathways, risk factors, epidemiology, diagnosis, treatment recommendations, and management challenges of NTM-PD. This narrative review was based on a synthesis of literature from the PubMed database using the search terms nontuberculous mycobacteria, NTM, nontuberculous mycobacterial pulmonary disease, NTM-PD, Mycobacterium avium, and Mycobacterium abscessus published until July 2023. The authors subjectively reviewed each publication and included those considered most relevant or robust in the review. Information was also retrieved from clinicaltrials.gov when deemed relevant.

2. NTM species

More than 200 NTM species and subspecies have been identified to date [10]. Although these organisms are closely related, they have distinct epidemiologic features and behavior as pathogens. The most relevant groups known to cause NTM-PD worldwide are M. avium complex (MAC) and M. abscessus (MAB) complex [11]. MAC is a group of slowly growing mycobacteria comprising 12 species (M. avium, Mycobacterium intracellulare, Mycobacterium chimaera, Mycobacterium colombiense, Mycobacterium arosiense, Mycobacterium vulneris, Mycobacterium bouchedurhonense, Mycobacterium timonense, Mycobacterium marseillense, Mycobacterium yongonense, Mycobacterium paraintracellulare, and Mycobacterium lepraemurium), whereas MAB organisms are rapidly growing mycobacteria comprising three subspecies (M. abscessus subspecies abscessus, M. abscessus subspecies bolletii, and M. abscessus subspecies massiliense). Following MAC and MAB, Mycobacterium xenopi, Mycobacterium fortuitum, and Mycobacterium kansasii are the next most common causes of NTM-PD [11], and other notable species include Mycobacterium malmoense, Mycobacterium simiae, and Mycobacterium szulgai [12].

3. Environmental sources and transmission pathways

NTM infections are primarily acquired from the environment. NTM organisms can grow in natural as well as artificial water environments (Table 1). The soil [23–25], plants [26,27], air [17,28,29], and dust [23,30,31] are also sources of NTM. Inhalation of aerosolized NTM-contaminated water droplets or soil is considered the primary source of transmission of pathogenic NTM species to humans [32]. As such, it should not be surprising that the prevalence of NTM-PD varies regionally, with higher rates in coastal areas compared to continental areas [33–37]. Warm, humid environments with high atmospheric vapor pressure contribute to population risk [11,38], as does exposure to air pollution [39]. Variations in temperature and rainfall may also play a role in environmental exposure to some species of NTM [40]. In fact, there is potential for increased exposure to these pathogens during natural disasters [41] with increased NTM infections linked to hurricanes [42].

Table 1. Potential sources of NTM in natural and artificial water environments.

Natural water environments [13,14]	Artificial water environments
Lakes Rivers Streams Brooks Seawater	Wastewater treatment plants [15] Drinking water pipelines [16] Bottled and municipal water [16] Residential and hospital faucets [17,18] Showerheads [19] Hot tubs [20] Ice machines [21] Humidifiers [5] Heating/ventilation systems [5] Spa foot-baths [22]

Prolonged exposure to NTM-contaminated environments, such as certain occupational or recreational settings involving exposure to dust, soil, or water sources, as well as activities like farming, gardening, public bath use, swimming, and hot tub use, can increase the risk of infection [5,43–46]. Healthcare-associated transmission has also been observed in both the inpatient and outpatient settings [21,47–50]. Lastly, there have been rare instances of potential person-to-person transmission reported, particularly in individuals with compromised immune systems [51]. NTM exposure does not always lead to infection or disease. Susceptibility to NTM infections can vary among individuals and populations.

4. Risk factors

NTM-PD can affect any individual, but certain risk factors increase the likelihood of developing infections and disease. Infection often occurs in the setting of underlying structural airway disease as these conditions provide an environment conducive to NTM colonization. Bronchiectasis, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), pneumoconiosis, prior TB, pulmonary alveolar proteinosis, α-1-antitrypsin anomalies, and esophageal motility disorders have all been reported to increase the risk of NTM-PD [9,52]. In fact, 80% of the patients with NTM-PD in a large US managed care health plan had at least one underlying lung disease, of which COPD (53%), pneumonia (40%), bronchiectasis (37%), and asthma (23%) were the most common [53]. A recent meta-analysis that included 99 publications affirms the reported association between NTM-PD and various respiratory diseases as the odds ratio (OR) for NTM-PD was significantly increased for bronchiectasis (OR, 21.43), a history of TB (OR, 12.69), interstitial lung disease (OR, 6.39), COPD (OR, 6.63), and asthma (OR, 4.15) [54].

Of particular interest to NTM-PD are the underlying conditions causing structural lung damage such as CF, bronchiectasis, and COPD. The overall prevalence of NTM infection in patients with CF is 7.9% and is increasing over time based on international registry reports [55]. Clinically, NTM-PD increases the rate of CF pulmonary exacerbations three-fold [56] and accelerates deterioration of lung function [57–59]. In COPD patients, the risk of NTM-PD is nine-fold greater compared to those without obstructive lung disease [60]. NTM-PD is also associated with preceding use of inhaled corticosteroids in this population, with evidence for a dose–response relationship [61,62]. Infection doubles the rate of severe exacerbations requiring hospital admissions, leads to a significant deterioration in lung function, and increases the risk of mortality [33,63]. In patients with non-CF bronchiectasis, the global prevalence of NTM from 2006 to 2021 was estimated to be approximately 10% [64,65]. Elderly Caucasian women with a low body mass index seem to be more susceptible to NTM infection in non-CF bronchiectasis [66,67]. In recent years, accumulating evidence has confirmed that patients with an NTM infection or NTM-PD are more likely to have severe bronchiectasis (e.g., diffusely dilated airways, evidence of airflow obstruction, nodular densities often described as tree-in-bud abnormalities, cavities), frequent exacerbations, and higher mortality rates than those without NTM [67–69].

NTM-PD tends to be more prevalent in older individuals, with a higher incidence observed in those ≥65 years [53,60,70,71]. For example, a US study found that the overall annual prevalence of NTM-PD in 2015 was 17 per 100,000 persons but for people ≥65 years, it was 47 per 100,000 persons [53]. The reasons for the increased susceptibility in older age groups are not fully understood but may be due to age-related changes in lung structure and immune function [72]. Furthermore, intensive antimicrobial therapy in chronic disease states may affect the health of the respiratory microbiome, contributing to dysbiosis and potentially making the host more susceptible to NTM infection or disease [73,74].

Some studies have also found that women have a greater risk of NTM-PD compared to men [36,52,53,75–79]. For example, in 2015 the annual prevalence was 17 per 100,000 persons for women compared to the overall prevalence of 12 per 100,000 persons in the US [53]. In addition, Prevots et al. [75] found that the prevalence of NTM-PD was 1.1–1.6-fold greater among women relative to men across four different sites in the US. The reasons for this gender difference are not fully understood and may involve hormonal or genetic factors.

Immune system deficiencies or suppression can increase the risk of NTM-PD. This includes individuals with HIV/AIDS, organ transplant recipients, individuals on immunosuppressive medications, and those with inherited or acquired immunodeficiencies [9,11,52]. Certain genetic conditions that impact the immune response can also predispose individuals to NTM-PD, such as abnormalities of the interleukin-12/interferon-gamma axis, certain human leukocyte antigen alleles, and polymorphisms of solute carrier 11A1 (or natural resistance-associated macrophage protein 1) and vitamin D receptor [80].

The role of genetics in NTM-PD remains scant, but NTM-PD has been reported among families, suggesting there may be a heritable, genetic contribution to this disease [81,82]. Racial or ethnic disparities have also been reported in the literature. For example, Adjemian et al. [36] reported that prevalence among Asians/Pacific Islanders in the US was two-fold greater than among whites. In Hawaii, incidence and risk of NTM-PD are greater among people of Asian ethnicity and lowest among Native Hawaiians and Other Pacific Islanders [83,84], suggesting that biologic and behavioral factors can affect disease susceptibility.

Having one or more risk factors does not guarantee the development of NTM-PD as the interplay between environmental exposure, host susceptibility, and other factors contributes to the overall risk. Furthermore, the long-term outcomes, prognosis, and burden of NTM-PD can vary depending on several factors, including the specific NTM species involved.

5. Epidemiology

NTM infections are not generally subject to mandatory reporting in many countries, including Asia, Europe, and most of the US [85,86]. In fact, it is only notifiable in a few settings, including certain areas of the US, Australia, and Portugal [40,87,88]. This absence of systematic surveillance and reporting mechanisms for NTM-PD limits the availability of comprehensive epidemiological data and makes it difficult to capture the true burden. Moreover, NTM disease is not uniformly defined throughout studies with some reporting prevalence based on one NTM isolate (i.e., NTM infection) and others based on diagnostic codes or guideline criteria for clinically confirmed disease, which may include microbiologic findings, presence of pulmonary or systemic symptoms, and radiologic abnormalities in the lungs [6,85,89].

5.1. Global

NTM-PD is a global health concern as population-based data demonstrate a concerning trend of increasing prevalence worldwide [11]. A recent systematic review of 47 studies that included 285,681 NTM isolates from more than 18 countries found that 82% of the studies reported an increase in NTM infection and 68% reported an increase in NTM disease. The overall annual rate of change for NTM infection and disease per 100,000 persons was 4.0% and 4.1%, respectively, and a majority of studies reported an increasing trend for MAC infection (n = 15/19, 78.9%) and disease (n = 10/12, 83.3%) [90]. Factors influencing this observed increase in NTM infection and disease may include a higher level of physician awareness, improved detection methods, increased NTM exposure, greater host susceptibility including a growing population of immunocompromised and vulnerable individuals, as well as complex medical and surgical procedures [91,92]. The prevalence of NTM is increasing globally albeit with large regional differences as shown in Figure 1. There are also significant differences in predominant NTM species/groups across geographies (Table 2), with MAC being the dominant group of organisms in North America, Europe, Australia/New Zealand, and parts of Asia [11,96] and MAB organisms emerging as the predominant NTM pathogens in parts of Asia, including southern Taiwan [100]. While the reasons for these differences are unclear, climate, cultural practices, and healthcare systems may help account for epidemiological differences among geographies.

Figure 1. Annual prevalence (number of cases per 100,000 persons) of nontuberculous mycobacterial pulmonary disease across different geographies.

^aThe prevalence of pulmonary NTM colonization in apparently healthy and diseased individuals in sub-Saharan Africa was 7.5% based on a meta-analysis that included 37 articles.

Table 2. Summary of NTM species prevalence across different geographies.

NTM species	North America	Europe	Asia	Oceania	Africa	South America
MAC	51–85%	22–82%	34–76%	61–83%	9–58%	20–63%
MAB complex	3–18%	5–9%	7–45%	5–12%	7–16%	7–19%
M. fortuitum	<1–8%	6–63%	2–24%	8–12%	5–8%	4–16%
M. gordonae	12–13%	5–20%	6–9%	2%	1–17%	17%
M. xenopi	1–23%	6–28%	1%	N/A	1%	N/A
M. kansasii	1–5%	5–70%	2–13%	2–20%	3%	3–33%
M. chelonae	N/A	9%	6–30%	3%	N/A	N/A
M. malmoense	N/A	8–37%	N/A	N/A	<1%	N/A
Authors	Hoefsloot, van Ingen et al. 2013 [93]; Prevots and Marras 2015 [11]; Tsai Yunusa et al. 2022 [94]; Zweijpfenning, van Ingen et al. 2018 [95]	Dahl, Laursen et al. 2023 [96]; Hoefsloot, van Ingen et al. 2013 [93]; Prevots and Marras 2015 [11]; Zweijpfenning, van Ingen et al. 2018 [95]	Hoefsloot, van Ingen et al. 2013 [93]; Lee, Kim et al. 2021 [97]; Prevots and Marras 2015 [11]; Ryoo, Shin et al. 2008 [98]; Zweijpfenning, van Ingen et al. 2018 [95]	Hoefsloot, van Ingen et al. 2013 [93]; Prevots and Marras 2015 [11]; Zweijpfenning, van Ingen et al. 2018 [95]; Thomson, Furuya-Kanamori et al. 2020 [40]	Hoefsloot, van Ingen et al. 2013 [93]; Okoi, Anderson et al. 2017 [99]; Zweijpfenning, van Ingen et al. 2018 [95]	Hoefsloot, van Ingen et al. 2013 [93]; Zweijpfenning, van Ingen et al. 2018 [95]

Abbreviations: MAB, Mycobacterium abscessus; MAC, Mycobacterium avium complex.

5.2. North America

The prevalence of NTM-PD appears to be increasing in North America. Prevalence data from various US-based studies are shown in Table 3, indicating prevalence ranging from 1.4 to 47.5 per 100,000 persons depending on age and geographic location, and annual percent change in prevalence ranging from 2.7% to 9.9% [7,36,53,75,83,101–104]. Canada has shown similar prevalence to the US. Comprehensive population-based studies in Ontario demonstrated an annual disease prevalence of 10 cases per 100,000 persons in 2010. The average annual increase in disease prevalence was 6.3% between 1998 and 2010 [104]. Five-year prevalence data, which may estimate disease prevalence more accurately based on the chronic nature of the disease, revealed a prevalence of 41 per 100,000 persons over the period between 2006 and 2010, an increase from 29 cases per 100,000 persons between 1998 and 2002 [104].

Table 3. Summary of North American studies assessing the prevalence of NTM-PD.

Population	Time Period	Annual Prevalence^a	Period Prevalence^a	Annual % change in prevalence	Authors
Nationally representative sample of Medicare Part B beneficiaries (≥65 years of age)	1997–2007	20–47 over study period	112	8.2%	Adjemian, Olivier et al. 2012 [36]
Four geographically diverse integrated health care delivery systems in the US (California, Colorado, Pennsylvania, Washington)	2004–2006	5.5 (range: 1.4–6.6)	By age group: <60 years: 1.7; 60–69 years:15; 70–79 years: 30; >80 years: 57	2.7% (1994 to 2006)	Prevots, Shaw et al. 2010 [75]
Oregon surveillance data with laboratory results from Portland, Tri-County Region	2005–2006	5.6	8.6 By age group: ≥50 years: 20.4	N/A	Winthrop, McNelley et al. 2010 [7]
Kaiser Permanente beneficiaries residing in Hawaii	2005–2013	20–44 over study period	122 By age group: 50–64 years: 183; ≥65 years: 696; ≥75 years: 906	6%	Adjemian, Frankland et al. 2017 [83]
Five states with NTM reporting (Missouri, Mississippi, Maryland, Ohio, Wisconsin)	2008–2013	8.7–13.9 over study period	75.8	9.9% By age group: 50 to 80+ years: 11.8%; 0 to 49 years: 8.7%	Donohue and Wymer 2016 [101]
Large US managed care health plan	2008–2015	6.8–11.7 over study period By age group and gender: Women: 9.6–16.8 Men: 3.79–6.45 ≥65 years: 30.3–47.5 <65 years: 2.9–4.1 Medicare plan members: 19.5–43.1	N/A	7.5% (prevalence increased by at least 10% in 39 states)	Winthrop, Marras et al. 2020 [53]

Abbreviations: NTM, nontuberculous mycobacteria.

^aNumber of cases per 100,000 persons.

5.3. Europe

Prevalence of NTM-PD in Europe is lower compared to North America and Australia [11], but studies suggest that it is on the rise in several European countries including Spain [105], Portugal [87], Germany [106], the United Kingdom [107–109], and the Netherlands [110]. Schildkraut et al. [85] estimated the annual prevalence of NTM-PD in the European Union (EU)-4 (France, Germany, Italy, Spain) and the United Kingdom (UK) in 2016 using a two-round Delphi NTM-PD-expert consensus-building method at 6.2 cases per 100,000 persons in 2016. Regional prevalence estimates were made using an estimation model that incorporated data obtained from a blinded physician screening survey and a real-world NTM-PD treating-physician/patient-chart observational study. Prevalence per 100,000 persons was found to vary regionally within countries, ranging from 0.9 to 7.0 in the UK, 1.3 to 13.6 in France, 3.9 to 8.2 in Germany, 3.8 to 10.4 in Italy, and 3.3 to 8.4 in Spain.

5.4. Asia

Studies show that the prevalence of NTM-PD in East Asia is increasing, including South Korea, Japan, and Taiwan, especially among large tertiary care centers [77,79,97,111–118]. In fact, a systematic review and meta-analysis that was conducted to estimate the prevalence of NTM in adults with non-CF bronchiectasis reported that the pooled NTM prevalence of six East Asian studies (China, Japan, Korea) was 7.5% greater than that of the eight studies from other countries (Egypt, France, Greece, Israel, Italy, Netherlands, Pakistan, US) in adults with non-CF bronchiectasis [65].

In South Korea, one study estimated that NTM infection prevalence estimates increased five-fold from 2007 to 2016 [113] where the 2016 prevalence estimates were 33.3–39.6 cases of NTM infection per 100,000 persons [113,114]. In Japan, the annual national NTM-PD prevalence was estimated at 24.9 cases per 100,000 persons for the entire country [85] and several studies conducted out of hospitals reported the incidence of NTM-PD in Taiwan to range from 13 to 46 episodes per 100,000 patients [71,115].

5.5. Oceania

Studies conducted in different states of Australia have consistently reported rising rates of NTM infections [40,76,119,120]. In Queensland, Australia, all cases of mycobacterial infection (TB and NTM) are notifiable under the Queensland Public Health Act (2005), which provides an excellent opportunity for large-scale epidemiological research. In 2015, there was a notification rate of 25.9 cases per 100,000 persons and notifications had been increasing approximately 17% per year over the previous four years [120]. The estimated incidence rate increased 2.3-fold from 11.10 per 100,000 in 2001 to 25.88 per 100,000 in 2016 [40].

5.6. Africa

In a systematic review and meta-analysis of 37 articles, the overall prevalence of NTM in pulmonary samples in sub-Saharan Africa was 7.5%, including studies in western (Ghana, Mali, Nigeria), southern (South Africa, Zambia), and eastern (Ethiopia, Kenya, Tanzania, Uganda) Africa [99]. However, the lack of a reliable population denominator makes population prevalence estimates difficult. For example, among patients suspected of having TB, the overall prevalence of NTM isolation ranges from 1.7% in Kenya to 39.1% in Nigeria with Ethiopia, South Africa, and Zambia ranging from 2.7% to 15.1%. In a study conducted out of Kenya, the overall prevalence was 42.4% in patients retreated for TB, whereas mine workers in South Africa had a prevalence of 64.3–68.4%, and patients suspected of having an NTM infection in South Africa and Zambia had a prevalence from 59.3% to 100% [99].

5.7. South America

It is difficult to make conclusions regarding the population frequency of NTM-PD in South America. Based on studies conducted in Brazil, Prevots and Marras [11] suggest an annual prevalence of 1.3–5.3 cases per 100,000 persons for NTM isolation, 0.25–1.0 cases per 100,000 persons for NTM-PD, as well as a six-year period prevalence of NTM-PD of 1.5 cases per 100,000 persons from 2000 to 2005, and a ten-year period prevalence of 10 cases per 100,000 persons for NTM-PD from 1996 to 2005 [11]. More recent studies have assessed annual incidence, with an estimated annual incidence of NTM-PD in French Guiana of 1.07 cases per 100,000 persons [121]. This is similar to a study from Uruguay reporting an incidence of 1.57 cases per 100,000 persons in 2018, which increased from 0.33 cases per 100,000 persons in 2006 [122].

6. Clinical manifestations and diagnostic approaches

NTM-PD can present with a wide range of clinical manifestations that can be nonspecific and mimic any infectious process of the lungs [123]. However, most patients have a chronic, persistent, or recurring cough that may produce sputum, worsen over time, and can be associated with other respiratory symptoms such as dyspnea, hemoptysis, wheezing, chest pain, and systemic manifestations such as fever, fatigue, malaise, and weight loss [9].

The American Thoracic Society (ATS), European Respiratory Society (ERS), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and Infectious Diseases Society of America (IDSA) have released diagnostic criteria for NTM-PD that include clinical, radiographic, and microbiologic findings [6,124]. Microbiologic confirmation of NTM involves any of the following: (1) positive cultures from at least two separate expectorated sputum samples; (2) positive culture from at least one bronchial wash or lavage; or (3) a transbronchial or other lung biopsy with compatible histopathologic features, such as granulomatous inflammation or acid-fast bacilli, and a positive culture for NTM or ≥1 positive sputum or bronchial wash culture for NTM.

Correct species identification of NTM isolates is clinically important since NTM species differ in their potential to cause clinical disease and in their susceptibility to antimicrobials [125–127]. The most sensitive method to detect NTM from respiratory samples is culture using automated liquid culture systems (e.g. Mycobacteria Growth Indicator Tube (MGIT); BD Biosciences, Sparks, MD, USA) and solid media (e.g., Löwenstein-Jensen or Middlebrook 7H10 and 7H11 media) [91]. Microscopy should be routinely carried out using auramine-phenol staining as it allows the direct evaluation of mycobacteria and provides a useful adjunct to culture [128–131]. All NTM isolates from respiratory samples should be identified using validated molecular or mass spectrometry techniques [91]. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry has shown considerable promise in providing rapid speciation of NTM [132–136]. Unfortunately, some NTM-PD patients do not expectorate sputum [137] and the collection of respiratory specimens for culture and susceptibility testing can take weeks to months to obtain a result in many clinical settings [91]. Therefore, non-sputum, rapid identification and speciation techniques are needed to improve diagnostic and treatment capabilities [138].

The diagnosis of TB can be challenging due to the similarities in presentation and radiological findings to NTM disease. Therefore, differentiation is important to prevent misdiagnosis, and ensure proper care and infection control. Interferon gamma release assays (IGRAs) such as the T-SPOT.TB and QuantiFERON tests measure the amount of IFN-γ produced in response to in vitro stimulation of whole blood with specific M. tuberculosis antigens [139,140]. While they have a moderate positive rate for the diagnosis of NTM [141], they can help discriminate between TB and NTM disease [142,143]. NTM-specific IGRAs may also help to improve the diagnostics of NTM infections in affected patients [144]. The MPT64 test, a rapid immunochromatographic test that targets MPT64 protein in positive cultures by using anti-MPT64 monoclonal antibodies, has high sensitivity and specificity for TB [145,146]. It helps to differentiate between TB and NTM disease [147], especially when combined with MGIT960 cultures [148].

Serological testing has clinical utility in the diagnosis of NTM-PD. For example, in one study from Romania, NTM serodiagnosis correlated well with MAC culture results [149]. Several studies evaluating serum IgA against the glycopeptidolipid core antigen (a cell surface antigen that is found in MAC) have reported a sensitivity of 52–85% and a specificity of 91–100% using the optimal cutoff value of 0.7 U/ml [150–155]; serum IgA against the glycopeptidolipid core antigen also correlated with radiographical changes [156] and has been proposed as a potential biomarker of treatment response [157,158]. In addition, studies assessing assays that measure serum IgG against the mycobacterial antigen A60 have reported both sensitivity (87–95%) and specificity (73–95%) for the diagnosis of MAB infection in patients with cystic fibrosis [159,160]. If validated by larger studies in different cohorts, serological testing could find a potential application in clinical practice.

A real-time polymerase chain reaction (PCR) assay for the detection of MAC that targets the 16S-23S rRNA internal transcribed spacer has been found to be both sensitive (71%) and specific (99.5%) within 24 hours of specimen receipt, with a positive predictive value of 98%, and a negative predictive value of 90% [161]. Other molecular techniques available to detect NTM in respiratory specimens include PCR restriction analysis for the rpoB gene [162] and the GenoType Mycobacteria Direct test [163]. While their utility is somewhat limited at this time [91], two molecular assays based on the DNA/DNA hybridization technique (GenoType CM direct®, Bruker, Billerica, MA, USA and VisionArray Myco®, ZytoVision, Bremerhaven, Germany) may improve rapid identification of mycobacteria from clinical specimens; Schildhaus et al. [164] reported that these two tests had 73.0–89.2% sensitivity, 81.5–96.3% specificity, 86.8–96.4% positive predictive value, and 72.2–84.6% negative predictive value for 37 mycobacterial isolates including 11 TB and 26 NTM isolates.

In addition to developing new, more rapid diagnostic tests, an important research priority is investigating biomarkers associated with disease progression or response to treatment as it can inform clinical decision making [138,165]. Cell-mediated immune responses, rather than antibody responses, could provide an alternate approach for immunologic monitoring of treatment response. Kim et al. [166] reported that declining levels of IL-17 and IL-23 were associated with treatment failure in MAC pulmonary disease (MAC-PD), suggesting that continued impairment of the IL-17 pathway reflects ongoing disease processes. Carbohydrate antigen 19–9 (CA 19–9), a treatment monitoring biomarker for several forms of cancer, may also be a useful marker for monitoring therapeutic responses in NTM-PD. Hong et al. [167] reported that CA 19–9 levels significantly declined in patients with a treatment response within 12 months of therapy, while no difference was observed among patients without a treatment response. Blood-based biomarkers could provide valuable insights into the clinical management of NTM-PD as they are readily available throughout the course of treatment, offer precise measurements that are not reliant on hierarchical scoring systems (such as those used for radiographic findings or microbiology results), and may detect clinical responses that are subtle on physical examination, such as those that may be found with extra-pulmonary forms of NTM disease [165].

7. Guideline-based treatment recommendations

The current guideline-based treatments for NTM-PD are based on recently published recommendations provided by the ATS, ERS, ESCMID, and IDSA [6,124]. They provide susceptibility-based treatment recommendations for NTM-PD in adults (without cystic fibrosis or HIV infection) caused by the most common NTM pathogens including MAC, M. kansasii, M. xenopi, and MAB. An expert panel group has also provided consensus management recommendations for the treatment of less common NTM species including Mycobacterium chelonae, M. fortuitum, Mycobacterium genavense, Mycobacterium gordonae, M. malmoense, M. simiae, and M. szulgai [168]. As the focus of this paper is the most clinically relevant sources of NTM-PD, the treatment recommendations for MAC-PD and MAB pulmonary disease (MAB-PD) are included herein.

Treatment for MAC-PD involves a three-drug regimen that includes a macrolide (azithromycin is preferable to clarithromycin) and ethambutol for a minimum of 12 months after sputum cultures convert from positive to negative. This regimen should be provided three times weekly for noncavitary nodular bronchiectatic disease and daily for cavitary or severe/advanced nodular bronchiectatic disease. Parenteral amikacin or streptomycin is also recommended for patients with cavitary or severe/advanced bronchiectatic or macrolide-resistant MAC-PD for 2–3 months, and amikacin liposome inhalation suspension (ALIS), a polycationic, semisynthetic, broad-spectrum aminoglycoside, is recommended when treatment response is not achieved after six months [6,124].

Treatment of MAB-PD involves a combination of three or more antimicrobials, including macrolides, amikacin, and a β-lactam or imipenem. Disease caused by macrolide-susceptible strains should be treated with a macrolide-containing multidrug-treatment regimen. Disease caused by macrolide-resistant strains may still be treated with a macrolide as it can be used for its immunomodulatory properties, but it is not considered a member of the recommended three-drug regimen. Expert consultation is recommended to guide treatment length [6,124].

Adjunctive surgery is also an effective therapeutic option [169] for select patients with failure of medical management, cavitary disease, drug resistant isolates, or complications such as hemoptysis or severe bronchiectasis [6,124].

7.1. Other drugs under development for NTM-PD

Various other drugs for NTM-PD have reached clinical trials. In addition to being approved for refractory MAC-PD, ALIS is also being assessed as a first-line treatment for MAC-PD when provided with a background regimen in a Phase 3 trial (NCT04677569). Clofazimine, an antimicrobial phenazine dye indicated for leprosy, has in vitro activity against MAC and MAB [170]. Clinical trials report that it is a safe and reasonably tolerated therapeutic that achieves culture conversion and improved treatment outcomes in MAC-PD and MAB-PD [171–173]. As such, it is now recommended as a first-line oral treatment for MAB and an alternative treatment for MAC-PD in patients who are intolerant of first-line drugs [6,124]. Omadacycline (Paratek Pharmaceuticals Inc., Boston, MA, USA), a semisynthetic tetracycline antibiotic approved by the US FDA for the treatment of community-acquired bacterial pneumonia and skin infections [174], has shown in vitro activity against MAB, M. chelonae, M. fortuitum, and M. massiliense [175–177]; safety, efficacy, and tolerability are currently being assessed for MAB-PD in a Phase 2 trial (NCT04922554). Epetraborole (AN2 Therapeutics, Menlo Park, CA, USA), a boron-containing, small molecule inhibitor of bacterial leucyl-tRNA synthetase, has shown in vitro activity against MAC and MAB [178,179]; efficacy, safety, and pharmacokinetics in patients with treatment-refractory MAC-PD are being explored in a Phase 2/3 trial (NCT05327803). Finally, SPR720 (Spero Therapeutics, Inc., Cambridge, MA, USA), a novel aminobenzimidazole antibiotic that inhibits in mycobacteria the ATPase activity of DNA gyrase B (GyrB) [180–183], has shown in vitro activity against some of the major NTM organisms including MAC and MAB [180,184,185]; efficacy, safety, tolerability, and pharmacokinetics in MAC-PD are being explored in a Phase 2 trial (NCT05496374) along with pharmacokinetics with azithromycin and ethambutol co-administration and intrapulmonary pharmacokinetics in healthy volunteers in two Phase 1 trials (NCT05966688 and NCT05955586, respectively).

8. NTM-PD can be challenging to treat

Despite the increasing prevalence of NTM-PD, there is a relative scarcity of high-quality clinical trials evaluating treatment strategies. In fact, current treatment guidelines for NTM-PD are based on available clinical trial data for existing antibiotics [6] that have not been specifically developed for NTM infections [186]. Treatment generally involves multiple drugs for a prolonged duration [6,9,91,124], but even in the setting of prolonged combination therapy, outcomes are poor and mortality rates are high [171,187–193].

The exact number of people treated with guideline-based therapy for NTM-PD is challenging to determine as it depends on various factors; however, some studies show that once diagnosed, only 13–51% of individuals are treated with guideline‐based therapy [118,194–196], of whom only 41% continue at six months, 18% at 12 months, and 11% at 18 months [196]. Furthermore, in many cases, treatment is often not initiated for months to years after a diagnosis [118,192,196,197].

Sputum culture conversion occurs in 34–67% of patients receiving a susceptibility-based treatment regimen [187,190,192,198–201] and in only 11–21% of patients with macrolide-resistant strains [193,202]. Predictors of less favorable outcomes include older age, comorbidities, severe or cavitary disease, MAB infection, poor treatment adherence, drug intolerance, and adverse effects [199,203–210]. Even where culture conversion is achieved, recurrence rates have been found to occur in 25–49% [171,205,211–213], of which 25–54% are true relapses and 46–75% are reinfections [205,212,213].

Adverse drug reactions are very common during the treatment of NTM infections and are associated with treatment interruption or early treatment cessation [190,202,214,215]. For example, among patients enrolled in the US Bronchiectasis and NTM Research Registry, adverse effects occurred in 21% of therapy recipients, of whom 33% discontinued therapy [196]. This is somewhat lower than adverse event reporting in clinical trials [200,216], potentially due to underreporting [217,218].

A wide variety of adverse effects have been reported in the literature, especially among older patients [207]. Macrolides are often associated with gastrointestinal disturbance (e.g. nausea, vomiting, bloating, abdominal pain), decreased auditory acuity, tinnitus, QT prolongation, and hepatitis [186,190,219,220]. The most common rifamycin-induced adverse effects include hepatotoxicity, gastrointestinal disturbance, dermatitis, and immunologic reactions, including acute renal failure and thrombocytopenia [9,186,220,221]. The most well-documented adverse effects linked to ethambutol include ocular toxicity, optic neuritis, vision changes (e.g., blurred vision, color vision disturbance), increases in serum creatinine, and numbness and tingling in the extremities [186,220,221]. Finally, the primary clinical concerns with the aminoglycosides, such as ALIS, are respiratory in nature (e.g., dysphonia, cough, and dyspnea), along with ototoxicity, vestibular toxicity, and nephrotoxicity [186,222].

Various health-related quality of life side effects have also been reported including difficulty walking or interacting with others, fatigue or lack of energy, feelings of sadness or depression, and shortness of breath, wheezing, or other difficulties [223]. The potential for adverse effects and drug–drug interactions limits the tolerability and safety of treatment options, particularly in older individuals [202,203,207].

9. NTM resistance to antimicrobials

NTM species exhibit variability in drug susceptibility, and resistance to commonly used antimicrobial agents can occur. Resistance limits the therapeutic utility of current guideline-based treatments, which can lead to poor clinical outcomes [202,224–227]. NTM either naturally possess or develop high resistance against conventional antibiotics through a variety of mechanisms (Figure 2). They have several features that restrict drug uptake into the cell including a thick impermeable cell wall, as well as the formation of biofilms and granulomas [229]. They also utilize efflux pumps to remove unwanted molecules that may get inside the cell [230]; this efflux-mediated resistance has been reported for a variety of current guideline-recommended treatments such as macrolides [231–234], fluoroquinolones [235], rifamycins [231], and aminoglycosides [236], as well as other antimicrobials including tetracyclines [236–238], spectinomycin [239], and clofazimine and bedaquiline [240].

Figure 2. Nontuberculous mycobacterial antimicrobial targets and resistance mechanisms. Adapted from van der Laan, Snabilie et al. 2022 [228].

The enzyme catalyzed modification of antibiotics is a major mechanism of antibiotic resistance with β-lactams [241], fluoroquinolones [242], and aminoglycosides [243,244]. Further, functional Erm methyltransferases [245,246] and ADP-ribosylation [247,248] mediate intrinsic macrolide and rifamycin resistance, respectively. Some NTM species such as MAB pathogens are formidable due to inherent resistance mechanisms and the formation of biofilms [228,249]. Their exceptional multidrug resistance to standard antibiotics, including aminoglycosides, rifamycins, tetracyclines, and β-lactams [250], along with their ubiquitous environmental presence make them persistent pathogens that are extremely difficult to treat [251]. Other antibiotic factors, which may have a bearing on outcomes include whether the drug penetrates the pulmonary tissues and macrophages. Tissue penetration can be affected by the route of administration. Additionally, the environment within infected tissues and macrophages is acidic, with a pH range of typically 4 to 5 in macrophages and thus activity at this pH is essential.

Addressing these limitations requires ongoing research and development efforts to improve treatment outcomes for NTM-PD. This includes the development of novel oral antimicrobial agents with improved safety, tolerability, spectrum of activity, efficacy over shorter time periods, and minimal drug–drug interactions [252,253].

10. Conclusion

NTM infections are challenging and affect an increasing number of patients globally. The epidemiology is not uniformly reported, so absolute incidence is unknown. However, the ubiquitous nature makes them a constant threat among patients with structural lung damage. Diagnosis, both clinical and microbiologic, is essential to guide initial therapy which is usually at least 12 months of triple-drug therapy (MAC-PD) or ≥ 3 antimicrobials (MAB-PD) after sputum culture conversion to negative. Such complex therapy can be associated with adverse drug reactions, potential for drug–drug interactions, and development of antimicrobial resistance. New oral therapies active against MAC and MAB, including strains that are resistant to current agents, are urgently needed. This review highlights many of the ongoing challenges of treating patients with NTM-PD.

11. Expert opinion

NTM-PD is a global health concern as population-based data demonstrate increasing prevalence worldwide. A recent systematic review of 47 studies that included 285,681 NTM isolates from more than 18 countries found that 82% of the studies reported an increase in NTM infection and 68% reported an increase in NTM disease. NTM infections can present in a myriad of manifestations including chronic, persistent, or recurring cough that may produce sputum. This may worsen over time and can be associated with other respiratory symptoms such as dyspnea, hemoptysis, wheezing, chest pain, and systemic manifestations such as fever, fatigue, malaise, and weight loss.

Correct species identification of NTM isolates is clinically important since NTM species differ in their potential to cause clinical disease and in their susceptibility to antimicrobials. All NTM isolates from respiratory samples should be identified using validated molecular or mass spectrometry techniques.

Management of NTM infections has been recommended by various societies; treatment for MAC-PD involves triple-drug therapy including a macrolide and treatment for MAB-PD involves a combination of ≥3 antimicrobials including macrolides, amikacin, and a β-lactam or imipenem. The length of therapy, at least 12 months after sputum culture conversion to negative, is a major hurdle for adherence. The lack of well-controlled clinical studies further complicates the selection of appropriate therapy.

These challenges illustrate the requirement for new antimicrobials that are oral, well tolerated, and efficacious. NTM-PD is an increasing clinical and epidemiological challenge as the number of patients with structural lung disease and immunocompromised states increase globally.

Article highlights

• The microbiology of the NTM group of organisms is discussed to highlight the complexity of the pathogens.

• In addition to the widespread environmental presence of the organisms, the various risk factors for disease are presented.

• Global epidemiology is described from a wide range of countries, although the infections are generally not notifiable or routinely monitored.

• Laboratory diagnosis of NTM infections is a constant challenge, with new methods being developed to improve the accuracy and efficiency of identification of these infections, also potentially improving the evaluation of microbiologic response to therapy.

• NTM-PD is a growing clinical problem and as such, several key societies have produced clinical guidelines to assist clinicians with managing this difficult condition.

• Hurdles in treating NTM-PD are discussed, and new therapeutic agents under development are highlighted.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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Additional information

Funding

This paper was not funded.