Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms found in water, soil, and dust. More than 200 species have been identified up to till date although only a subset cause human disease (1). Over the last two decades, the global prevalence of pulmonary NTM disease has steadily increased, largely due to enhanced awareness, improved diagnostic techniques, an aging population, and the rising incidence of chronic lung diseases such as bronchiectasis and chronic obstructive pulmonary diseases (COPD) (2). Epidemiological studies show that the prevalence of NTM related bronchiectasis is about 10% in adults globally, in which Mycobacterium avium complex (MAC) is the most frequently isolated pathogen (3). Other clinically relevant species include M. abscessus, M. kansasii, and M. simiae (4, 5). NTM was initially thought to be an environmental organism but later gained importance as a potential opportunistic pathogen associated with both pulmonary and extrapulmonary infection (6, 7).

Pulmonary NTM infections and bronchiectasis are intricately linked and they exist as both cause and consequence of each other (8). NTM species, such as MAC, M. abscessus, and M. kansasii, cause chronic lung infections presenting with persistent cough, fatigue, and systemic symptoms (9). These infections flourish in structurally damaged lungs, where weakened mucociliary clearance and chronic inflammation helps to facilitate colonization of bacteria and disease progression. NTM infections significantly worsen respiratory outcomes in cystic fibrosis (CF) and other chronic pulmonary diseases and can be relative contraindications for lung transplantation (10). Increase in NTM prevalence shown by epidemiological trends have highlighted the growing clinical significance of these opportunistic pathogens (11).

Bronchiectasis act as both a risk factor for and a consequence of NTM infection, showing a bidirectional relationship (4, 12). Although, the bronchiectasis is well recognized, the clinical spectrum of disease remains heterogeneous and distinguishing colonization from true infection is still challenging (1). Post-tuberculosis lung diseases (PTLD) have emerged as a structural risk factor for NTM- pulmonary disease (NTM-PD) especially in TB endemic area like Asia. PTLD commonly results in fibrosis, cavitation, and traction bronchiectasis, all of which create a chronic niche that favors NTM colonization (13). Recent population-level assessments further demonstrate that a substantial proportion of TB survivors continue to experience long-term respiratory impairment, highlighting a growing burden of post-TB sequelae in Asia (14). Structural damage following healed TB has also been identified as one of the strongest predisposing factors for NTM infection across multiple cohorts, reinforcing its mechanistic relevance in disease susceptibility (15).

This review basically aims to synthesize current evidence on the epidemiology and pathogenesis of NTM-associated bronchiectasis, also to highlight diagnostic challenges specific to high TB- burden Asian settings and identify gaps in surveillance, diagnosis, and management requiring urgent attention. Our review focused on misdiagnosis and delayed management for NTM infections which can lead in rising global prevalence of NTM-associated bronchiectasis and data from high-burden, TB endemic regions has confirmed it. Our article aims to bridge this knowledge gap and highlight region-specific considerations. This article also emphasizes the urgent need to fulfill the diagnostic gap by enhancing diagnostic capacity, species-level surveillance, and targeted therapeutic strategies to improve patient outcomes and guide clinicians and researchers toward more precise, effective efforts to manage NTM-associated bronchiectasis.

This review was conducted to summarize and interpret the current evidence on the bidirectional relationship of NTM pulmonary disease (NTM-PD) and bronchiectasis, with a particular focus on Asian countries. Literature search was done by using major scientific databases, including PubMed, Scopus, Web of Science and Google Scholar covering articles published from 2008 to 2025. The search strategy combined Medical Subject Headings (MeSH) and keywords: (“nontuberculus mycobacteria” OR “NTM” OR “atypical mycobacteria”) AND (“bronchiectasis”) AND (“pathogenesis” OR “treatment” OR “epidemiology”). For regional focus, we added: (“India” OR “South Asia” OR “Asia-Pacific”). These were included to capture relevant studies which show regional prevalence and diagnostic challenges.

These included studies were selected on the basis of their relevance to NTM-associated bronchiectasis and data describing pathogenesis, epidemiology, diagnostic methods, treatment outcomes, and disease prognosis were extracted. References from the key were further screened to identify additional literature not retrieved during the initial search. Articles focused exclusively on Mycobacterium tuberculosis complex (MTBC) or extrapulmonary NTM infections were excluded.

NTM and bronchiectasis are closely related as they can lead to each other and result in bronchiectatic illness. MAC and M. abscessus are the most isolated in bronchiectasis-associated NTM-PD, even though their epidemiology is confounded by biases in detection and reporting. NTM-PD infections are clinically presented as highly variable and often non-specific. Its common symptoms include chronic cough, sputum production, fatigue, losing weight, hemoptysis, dyspnea, and night sweats (16). NTM-PD commonly showed nodular/bronchiectatic and fibro-cavitary (FC) forms being the primary manifestations (17). NTM disease involves tree-in-bud opacities, pulmonary cavitary lesions, nodules, and mucus plugging, with frequent involvement of upper lobes and multiple lung lobes (18). Clinical presentation may mimic other chronic lung conditions, which can delay diagnosis (19). For example, one of the disease as The Lady Windermere syndrome caused by MAC, is often seen in elderly women without underlying structural lung disease (20).

M. abscessus forms biofilm which further complicates disease progression by enhancing antibiotic tolerance and immune evasion (21). It forms chronic inflammation and repeated infections result in progressive bronchiectasis and irreversible airway damage (17). There is subtle appearance of symptoms in early disease but further these symptoms proliferate with chronic infection which causes significant morbidity. Two major patterns are recognized radiologically. First one is nodular/bronchiectatic form which is the most frequent and typically affecting thin, older, non-smoking women. It is also often localized to the middle lobe or lingula, and associated with multifocal bronchiectasis and small nodules (1, 4). This form progresses slowly but can lead to cumulative lung damage. The second form is FC disease, which involves upper lobes, resembles pulmonary TB, and is associated with a higher bacterial burden and faster progression, often occurring in older men with COPD or a smoking history (5).

Other less common presentations of bronchiectasis include solitary pulmonary nodules, extensive or disseminated disease, and hypersensitivity-like pneumonitis (4). Disseminated disease is rare but occurs in immunocompromised patients, while skin, bone, and lymph node involvement have been reported (22). Radiological severity scores and features such as tree-in-bud pattern, multilobar involvement, and bilateral disease are notable predictors of NTM positivity in bronchiectasis cohorts (23). Co-infections with pathogens like Pseudomonas aeruginosa, Staphylococcus aureus, and Acinetobacter baumannii are frequent and further complicate disease course (4). Overall, the spectrum of NTM-PD ranges from indolent nodular disease to aggressive cavitary and disseminated forms, and clinical manifestations must always be interpreted alongside radiological and microbiological findings to confirm true disease.

Multiple risk factors predispose individuals to NTM related diseases. At the host level, advanced age, female sex, low body mass index, anemia, and hypoalbuminemia have been consistently associated with NTM positivity (5, 11). Immune dysregulation, including HLA defects and impaired macrophage function, increases susceptibility, while systemic immunosuppression due to diabetes, malignancy, or transplantation further enhances risk (4). A Korean nationwide cohort confirmed that bronchiectasis itself is a strong independent risk factor, conferring a nearly 19-fold increased risk of NTM-PD compared with the general population (12).

Patients with NTM must exhibit new or worsening pulmonary symptoms, radiographic evidence (nodules, cavitary lesions, or bronchiectasis), and microbiologic confirmation (positive cultures from sputum or bronchoalveolar lavage, or granulomatous histology) (19). Risk factors include chronic lung diseases such as COPD, CF, interstitial lung disease, and non-CF bronchiectasis. Older age, female sex, low body mass index, gastroesophageal reflux disease, and greater lobar involvement are significantly associated with NTM infection (17). Ciliary dysfunction, whether primary (genetic) or secondary (post-infectious, smoking-related), impairs mucociliary clearance and increases susceptibility to NTM (20).

Prior TB also remains one of the strongest predisposing factors for NTM-PD in TB endemic regions. This is largely due to residual structural abnormalities such as fibrosis, cavitation, and airway remodeling. In such condition, the fibro cavitary pattern is commonly observed and reflects a form of post-TB lung damage that compromises mucociliary clearance and creates an environment conducive to microbial persistence (31, 32). This pattern may occur alongside or evolve into bronchiectasis through chronic inflammation, airway instability, and progressive epithelial injury. Studies from Asian cohorts further support this association, demonstrating that fibro cavity post TB disease significantly increases vulnerability to NTM infection compared to individuals with structurally normal lungs (9, 12). Thus, in high TB-burden regions, fibro cavitary sequelae represent a key risk factor for NTM-PD and help explain the characteristic radiological phenotypes observed in South Asian patients.

At the pulmonary level, prior history of TB, COPD and structural bronchiectasis are recognized as major risk factors for NTM (29, 33). Radiological features such as tree-in-bud opacities, multilobar disease, and cavitary lesions also correlate with higher risk of NTM (5, 23). Long-term macrolide prophylaxis in bronchiectasis patients, while effective in reducing exacerbations, has been linked to higher incidence of NTM disease, likely through selective antimicrobial pressure (12). Environmental exposure is central to pathogenesis, especially household water systems, biofilms in showers, indoor swimming pools, humidifiers, and soil are important reservoirs of NTM (34). Aerosolized exposure from these niches has been epidemiologically associated with pulmonary disease, and even genetic matches have been demonstrated between patient isolates and household strains. This highlights the interplay between environment, host vulnerability, and structural lung damage in the development of disease.

The diagnosis of NTM pulmonary disease remains complex because NTM can exist as mere colonizers in damaged lungs or as true pathogens causing progressive disease. According to international guidelines, confirmation requires a combination of clinical symptoms, radiological abnormalities, and microbiological evidence, with at least two positive sputum cultures or one positive bronchoscopy sample as mentioned in Figure 1. Diagnostic challenges persist due to overlapping symptoms with other lung diseases and heterogeneity in clinical markers (17). Diagnosis requires a combination of clinical, radiological, and microbiological criteria, including positive cultures from sputum or bronchoalveolar lavage and imaging findings such as nodular bronchiectatic or FC patterns (8). It symptoms overlap with other lung diseases, repeated cultures and molecular testing are often essential for confirmation (35). Molecular assays and sequencing are increasingly used for rapid species-level identification, although culture remains the gold standard for NTM (36). Distinguishing colonization from active infection is crucial, as unnecessary treatment exposes patients to toxic multidrug regimens, while delayed therapy risks irreversible lung damage (4).

There are some also radiological tests like high resolution CT (HRCT), which plays a supportive role in evaluating suspected NTM pulmonary disease. HCRT alone cannot confirm NTM but studies showed that features like tree-in-bud nodules, consolidation, and atelectasis significantly improve diagnostic specificity for NTM (37). Early cavity or consolidation on CT may predict disease progression in nodular- bronchiectatic MAC cases (38). So, it can provide patterns ranging from FC changes in structurally damaged post-TB lungs to nodular–bronchiectatic involvement in milder disease forms. HRCT offers valuable diagnostic information; however, it inevitably has its limitations. Findings such as tree-in-bud nodules, consolidation, and atelectasis can be observed in both NTM and TB cases. The FC and nodular bronchiectatic (NB) types are the two main radiological patterns of non-tuberculous mycobacterial pulmonary disease (NTM-PD). A key differentiation is that the post-TB FC-type NTM disease is often found in older aged men with pre-existing pulmonary conditions (like COPD or previous TB disease), while the NB-type without TB history typically affects postmenopausal, non-smoking women with intrinsic susceptibility due to poor cell mediated immunity (37–39) (Figures 2, 3).

Novel diagnostic approaches, including serological testing for glycopeptidolipids and dual skin tests, are under investigation to improve detection sensitivity for NTM (19). Next-generation sequencing (NGS) has revolutionized diagnostics by enabling rapid and precise species identification, as well as detection of resistance genes directly from clinical specimens (40). NGS also provides insight into the airway microbiome, resistance evolution, and treatment response prediction-laying the foundation for personalized therapy in NTM pulmonary disease.

In South Asia, molecular assays are increasingly improving NTM detection beyond conventional culture. Indian LPA assays have shown clear utility in differentiating M. tuberculosis from major NTM species in bronchiectasis cohorts, reducing misclassification (41). Multi-gene sequencing approaches also demonstrate high diagnostic yield; in a recent evaluation of 59 isolates, sequencing positivity reached 89.8% for 16S rRNA and combined 16S+rpoB analysis achieved the highest agreement with MALDI-TOF MS (kappa 0.76) (42). Together with Indian data showing wider adoption of PCR-based identification, these findings highlight the growing epidemiological relevance of molecular detection in TB-endemic regions.

Accurate detection of NTM-associated bronchiectasis remains a major challenge across South Asian countries due to limitations in laboratory infrastructure, inadequate diagnostic algorithms, and frequent misclassification as TB (Table 3). Most diagnostic laboratories in this region still depend on smear microscopy and conventional culture methods, which are insufficient for species-level identification or for differentiating NTM from M. tuberculosis (40, 43, 44). As a result, a significant proportion of NTM infections are either overlooked or incorrectly treated as drug-resistant TB, leading to delayed therapy, poor clinical outcomes, and unnecessary exposure to anti-tubercular drugs. This misdiagnosis is particularly problematic in patients with structural lung diseases like bronchiectasis, where chronic airway colonization by NTM often mimics active TB both clinically and radiologically (40, 45).

The diagnostic landscape is further complicated by the limited availability of advanced molecular tools such as sequencing, line probe assays, and MALDI-TOF mass spectrometry, which remain largely restricted to specialized or tertiary care centers (43–45). The peripheral and district-level laboratories, where the majority of patient first present, often lacks the capacity for species-level identification or drug susceptibility testing, resulting in under-diagnosis and underreporting of NTM disease. Additionally, RGM, which are clinically significant in bronchiectasis progression, are frequently dismissed as contaminants due to insufficient diagnostic capabilities, despite their distinct therapeutic implications (40, 42, 43).

Another critical gap is the persistent lack of clinical awareness and structured surveillance systems. In many south Asian countries NTM-PD infections are only diagnosed after multiple time failure of anti-TB regimens and many physicians rarely consider NTM in cases of chronic or recurrent pulmonary disease (40, 43). Furthermore, National TB programs typically do not integrate NTM detection into their workflows, and environmental surveillance data remain scarce, despite strong evidence linking water and soil exposure to NTM transmission. This absence of epidemiological data limits understanding of species distribution, regional prevalence, and resistance patterns, thereby hindering the development of tailored diagnostic strategies and public health policies.

Treatment of NTM lung disease, particularly MAC, is prolonged, costly, and often associated with significant drug-related toxicities. Standard therapy requires a three-drug macrolide-based regimen including a rifamycin, ethambutol, and a macrolide, given either daily or intermittently depending on disease severity (46). Recent advances in understanding the microbiology and host–pathogen interaction of NTM have led to the development of new therapeutic modalities. The initiation of inhaled amikacin liposome inhalation suspension (ALIS) represents one of the most significant innovations for patients with refractory MAC disease. Randomized controlled trials demonstrated that ALIS, when added to guideline-based therapy, significantly increased sputum culture conversion rates in treatment-refractory MAC pulmonary disease (47). ALIS has now been approved by the U.S. FDA for this indication, offering a targeted delivery system that enhances drug concentration at the site of infection while minimizing systemic toxicity (48). The M. kansasii and M. xenopi infections tend to have more favorable outcomes when treated with rifampicin- and macrolide-based regimens (9, 47). In high TB-burden Asian settings, many patients with NTM-associated bronchiectasis initially receive empirical anti-TB therapy because CBNAAT and smear microscopy cannot differentiate MTBC from NTM. This leads to delayed initiation of appropriate regimens and worsening lung destruction. Severe drug intolerance and incomplete treatment adherence are common due to the prolonged regimen and limited counseling support in resource-limited centers.

Beyond antibiotics, bacteriophage therapy has emerged as a promising adjunctive approach for multidrug-resistant M. abscessus and M. avium infections. Despite guidelines based multidrug therapy, treatment outcomes in MAC associated lung diseases remain suboptimal, with high recurrence rates and significant toxicity concerns (49). Recent advances focus on optimizing macrolide-based regimens and incorporating inhaled or parenteral amikacin for refractory disease to improve culture conversion and limit resistance. Alternative and emerging antimicrobials, including clofazimine and bedaquiline, show promise in difficult-to-treat cases through synergistic bactericidal activity, although controlled clinical evidence is still limited (50). Early compassionate-use case reports have shown improvement in culture conversion and clinical outcomes with the use of specific mycobacteriophages, although standardized protocols and regulatory approvals remain pending (26). Immunomodulatory strategies are gaining interest, particularly given the role of host immune dysfunction in NTM persistence. Agents such as interferon-gamma, vitamin D supplementation, and targeted cytokine modulators are under investigation to enhance macrophage activation and improve pathogen clearance (12). Macrolides, aside from their antimicrobial effect, continue to serve as immunomodulators reducing neutrophilic inflammation in bronchiectatic lungs (47). Access to species-specific drugs such as ALIS, clofazimine, macrolides, and bedaquiline is highly restricted due to regulatory constraints, high cost, and lack of inclusion in existing national program ie. National Tuberculosis Elimination Program in India.

Treatment outcome may also vary according to the underlying disease etiology. Patients with post-TB structural lung disease or fibro cavitary involvement often require longer, more intensive regimens and show lower treatment success, whereas those with localized nodular bronchiectatic disease tend to respond more favorable to standard macrolide based therapy (31, 51). Recognizing these etiological differences helps clinicians individualize therapy beyond standard recommendations.

The pathogenesis of NTM-PD in the context of bronchiectasis is a multifactorial process driven by complex interactions between host airway structure, immune defense, microbial adaptation, and environmental exposure (21). Among these, bronchiectasis characterized by irreversible airway dilation, mucus stasis, and impaired mucociliary clearance which plays a pivotal role in creating a permissive niche for NTM colonization and persistence (9, 52). In this way it creates favorable structural conditions for NTM colonization, but only a proportion of patients progress to active diseases (32). This heterogeneity is influenced by host susceptibility factors, environmental exposure, and pathogen specific virulence rather than bronchiectasis alone. Thus, bronchiectasis serves as a permissive condition but is not sufficient by itself for NTM-PD development.

The relationship between NTM and bronchiectasis is inherently bidirectional, forming a pathological cycle in which each condition predisposes to and amplifies the other. This interaction is increasingly recognized as a critical determinant of disease persistence, severity, and clinical outcomes. NTM are ubiquitous environmental organisms that opportunistically infect the airways, particularly in hosts with structural lung abnormalities. Whereas, bronchiectasis is characterized by irreversible airway dilation and impaired mucociliary clearance so it provides a niche environment where inhaled NTM can adhere, colonize, and evade host defense mechanism (53). The impaired clearance of mucus and reduced ciliary function facilitate bacterial persistence and biofilm formation, allowing NTM to resist both immune-mediated clearance and antimicrobial therapy (52). Mechanistically, bronchiectasis predisposes to NTM acquisition through impaired mucociliary clearance, chronic neutrophilic inflammation, and airway distortion that promotes biofilm formation (32, 54). NTM infection leads to epithelial injury and cytokine driven granulomatous inflammation, accelerating airway remodeling and worsening bronchiectasis (46).

Chronic NTM infection, in turn, drives sustained inflammation and tissue destruction through cytokine release and granulomatous reactions, causing further architectural distortion of the airways and progression of bronchiectasis (55). Clinical evidence strongly supports this vicious cycle model (Figure 4). A significant proportion of bronchiectasis patients which is ranging from 9% to 50% that harbor active NTM infections, while conversely, NTM infection itself can initiate or accelerate bronchiectatic changes (9, 51). Repeated episodes of infection promote epithelial damage, mucus hypersecretion, and immune dysregulation, perpetuating airway remodeling (9, 32). This cycle is further compounded by the fact that immune suppression, use of inhaled corticosteroids, and co-existing conditions such as COPD or cystic fibrosis (CF) substantially increase susceptibility to both bronchiectasis and NTM-PD (55).

Biofilm formation by NTM within bronchiectatic airways not only enhances persistence but also facilitates horizontal gene transfer, potentially increasing antimicrobial resistance and complicating treatment outcomes (52). These resilient microbial communities stimulate chronic neutrophilic inflammation, leading to progressive lung destruction (51). Over time, the interplay between host structural vulnerability and pathogen adaptation shapes a feedback loop that is clinically evident as worsening lung function, recurrent exacerbations, and increased mortality (54). Understanding this bidirectional pathogenic loop is vital for clinical management, as interventions targeting only the infection or the structural disease in isolation are unlikely to achieve optimal outcomes. A comprehensive approach, combining aggressive antimicrobial therapy, airway clearance strategies, and modulation of inflammation, is essential to interrupt this cycle and improve patient prognosis.

The prognosis of NTM-PD is heterogenous in nature and it is influenced by numerous factors like host immune status, lung abnormalities, infecting species and co-morbid conditions (9, 12). This causes stability in mortality and relapse rate especially in patients with advanced bronchiectasis, cavitary lesions, or immunosuppression and also underscore the chronic and progressive nature of the disease (32). A nationwide Korean study have shown that bronchiectasis patients were 19-fold higher risk of developing NTM-PD compared with the general population which highlighted the persistent vulnerability and recurrent nature of infection (12). The prognosis varies markedly by species like as MAC infections demonstrate moderate responses to macrolide-based therapy, with sputum culture conversion rates ranging from 50% to 65%, while M. abscessus complex infections are notoriously difficult to treat, often requiring prolonged multidrug regimens including parenteral aminoglycosides and associated with relapse rates exceeding 40% (47, 52). Some studies have also shown that same species have sub-species level variation in antimicrobial susceptibility patterns which influence outcomes, for example, inducible macrolide resistance in M. abscessus subsp. abscessus contributing to higher relapse rates and lower cure rates than other sub-species (52).

Several clinical and radiological parameters serve as predictors of poor prognosis, including cavitary disease, bilateral involvement, extensive nodular–bronchiectatic patterns, low body mass index, and delayed sputum culture conversion (5, 9). Chronic infection and persistent airway inflammation contribute to progressive lung function decline over time, even in patients who achieve microbiological clearance (32). Relapse is frequently driven by reinfection with new NTM strains rather than reactivation of the original isolate, reflecting continuous environmental exposure and incomplete host defense (2, 56, 57). The long-term clinical burden extends beyond microbial persistence. Due to chronic cough, sputum production, fatigue and frequent exacerbations, patients experience sustained quality of life impairment (12, 57). In such a condition, there is requirement of multip-sectorial approaches, nutritional and psychological care to mitigate disease progression and improve patient outcomes.

Our review has shown that there is a cyclic loop between bronchiectasis and NTM-PD and for breaking this loop, targeted antimycobacterial therapy is required. For this purpose, regular surveillance of bronchiectasis patient is needed as they are more compromised by NTM. But many studies have shown that there are diagnostic gaps due to misdiagnosis of NTM as TB and limited laboratory infrastructure especially in south Asian regions. Some studies have also shown that reinfection with new NTM species is more common among pre-existing chronic lung diseases or bronchiectasis. So, multidisciplinary approaches and management are required to fill the diagnostic gaps. There is need to identify NTM infection early in immunocompromised patients or patients earlier infected with TB as they are more vulnerable to NTM-PD infection. Establishment of species-specific surveillance system integrating NTM testing into National TB Elimination Programme and enhancing clinician awareness will be key steps for reduction in misdiagnosed cases and improvement of patients' outcome. Advancement in molecular technology especially multiplex-PCR and sequencing will further enable in precision of medicine approaches ensuring timely intervention and better therapeutic success in managing NTM associated bronchiectasis.