Nontuberculous mycobacteria (NTM) can cause inflammatory pulmonary disease, most commonly presenting as nodular-bronchiectatic (NB) disease or, less frequently, fibrocavitary (FC) disease in individuals with preexisting structural lung abnormalities or immunocompromised status [1,2]. In most regions, Mycobacterium avium complex (MAC) is the predominant pathogen in nontuberculous mycobacterial pulmonary disease (NTM-PD), followed by Mycobacterium abscessus species complex (MABS) and Mycobacterium kansasii[3,4].

Over the past two decades, the global incidence of NTM-PD has increased. Incidence rates rose in Denmark from 0.4 to 1.3 per 100000 population between 2000 and 2017 and in the United States from 3.13 to 4.73 per 100000 person-years between 2008 and 2015 [5,6]. Notably, reported rates have been higher in East Asia. In Japan, the incidence of NTM-PD increased from 15.8 to 19.2 per 100000 person-years between 2013 and 2017, representing a 17.7% increase [7]. In South Korea, prevalence rose from 11.4 to 56.7 per 100000 population between 2010 and 2021, a nearly 5-fold increase [8]. Mortality also remains substantial, with a 15-year cumulative mortality of 36.4% in South Korea and an 8-year all-cause mortality of 45.2% in Taiwan [9,10].

Increased mortality in patients with NTM-PD has been associated with cavitary lesions, including cavitary lesions within the NB pattern, hereafter referred to as cavitary NB pattern, which is associated with an approximately 2-fold higher mortality risk [9,11]. Accordingly, current guidelines recommend early antibiotic therapy not only for FC disease but also for patients with cavitary NB pattern at baseline [2,12,13].

Compared with patients with fibrocavitary (FC) NTM-PD, patients with nodular-bronchiectatic (NB) disease usually have a more indolent course and lower bacterial burden, but they are prone to persistent culture positivity without treatment [11,14]. Among patients with NB-pattern NTM-PD, cavitary NB disease, reported in 10.8–22.3% of cases, is a significant risk factor for radiographic progression and clinical deterioration requiring treatment [11,15]. Given that approximately 70–90% of patients with NTM-PD in Taiwan, South Korea, and Japan exhibit the NB pattern – characterized by bronchiectasis, bronchiolitis, and nodules – our understanding of the clinical course and predictors of progression beyond cavitation in this phenotype remains limited [3,14,16,17].

Host immune responses to pathogen interactions in NB-pattern NTM-PD may be crucial determinants of disease course. As a biomarker of immune exhaustion, elevated levels of circulating CD4+ lymphocytes expressing programmed death-1 (PD-1) have been reported to correlate with severe disease and radiographic progression in patients with NTM-PD [18]. Moreover, a recent Taiwan cohort study of patients with NB-pattern NTM-PD found that blood levels of soluble PD-1 (sPD-1) were negatively correlated with cavitary NB lesions and disease progression [15]. Unlike PD-1 expressed on T cells, sPD-1 is generated through alternative splicing that eliminates the transmembrane domain and can be measured directly in blood [19]. sPD-1 is believed to counteract immune exhaustion by inhibiting the interaction between membrane-bound PD-1 and its ligands. However, the generalizability and reproducibility of the association between circulating sPD-1 levels, cavitary NB lesions, and disease progression beyond a single-country cohort remain uncertain. Therefore, we conducted a multicountry cohort study in East Asia, including patients from Taiwan, Japan, and South Korea, to externally validate the association of blood sPD-1 levels with the cavitary NB phenotype and disease progression requiring treatment in patients with NB-pattern NTM-PD.

In this large multicountry cohort study, patients with NB-pattern NTM-PD had lower sPD-1 levels than healthy controls. Among patients with NB-pattern NTM-PD, those with cavitary NB pattern, who represented 15% of the cohort, had even lower sPD-1 levels than those with noncavitary NB pattern. During follow-up, disease progression requiring anti-NTM therapy occurred in 167 patients (42.9%). In the primary time-to-event analysis, lower baseline sPD-1 levels were independently associated with an increased risk of disease progression requiring treatment within 3 years. Directionally consistent associations were also observed in the analysis of early disease progression within 1 year, supporting the potential prognostic role of sPD-1. Collectively, these findings externally validate sPD-1 as a marker associated with the cavitary NB phenotype at baseline and subsequent disease progression, supporting its potential role in risk stratification in patients with NB-pattern NTM-PD.

These findings are consistent with previous evidence suggesting that immune exhaustion, a key determinant of NTM-PD severity, may be associated with sPD-1 levels [15,24]. Our study demonstrated a graded association between sPD-1 levels and disease progression, with patients in the lowest sPD-1 tertile showing the greatest risk of requiring anti-NTM therapy. This finding may be explained by the immunomodulatory role of sPD-1 as a PD-1 pathway antagonist, which may be associated with impaired T-cell function and disease progression [24,25]. In multivariable analysis adjusted for other significant factors, low sPD-1 remained independently associated with disease progression, suggesting an association beyond potential confounding. Although the causal relationship and underlying mechanism linking sPD-1 to NTM-PD severity and progression warrant further investigation, our multicountry validation cohort in Asia supports the use of sPD-1 at diagnosis as a prognostic marker for disease progression and suggests potential clinical applicability.

Recent studies suggest that chronic NTM-PD, possibly through persistent antigenic stimulation, upregulates PD-1 expression on CD4+ T cells, which is associated with higher bacterial burden, positive sputum smears, and more severe radiographic manifestations, including cavitary lesions [18,26]. Because sPD-1 is a circulating form of the immune checkpoint molecule PD-1, generated by alternative splicing and acting as a decoy receptor, it may mitigate the inhibitory effects of ligand binding to membrane-bound PD-1 on T-cell function [27,28]. Consequently, lower plasma sPD-1 levels may reflect greater T-cell exhaustion and impaired cellular immunity [29]. Furthermore, immune exhaustion impairs the host's capacity to generate effective T helper 1 responses and produce interferon γ, both of which are critical for controlling mycobacterial infection [30].

Interestingly, lower sPD-1 levels were associated not only with disease progression requiring anti-NTM therapy but also independently with the presence of cavitary NB-pattern NTM-PD, even after adjustment for age, sex, BMI, smear positivity, and NTM species. This finding suggests that immune exhaustion, reflected by low sPD-1 levels, may be associated with cavitary disease in NB-pattern NTM-PD, although the underlying mechanism remains unclear [15,18]. Nevertheless, the independent association of low sPD-1 with cavitary disease, even after adjustment for other risk factors, underscores its potential as a biomarker of advanced immune dysfunction in NTM-PD.

Unlike previous studies that primarily emphasized mortality prediction, such as the BACES score [31], our findings highlight sPD-1 as a novel predictor of disease progression, complementing established factors such as cavity formation and acid-fast smear positivity [2]. Most NB-pattern cases are noncavitary at diagnosis, approximately 85% in our study, and their clinical trajectory remains difficult to predict. Notably, the current ATS/ERS/ESCMID/IDSA guideline for NTM-PD management provides no clear recommendations on how to conduct watchful waiting in patients with noncavitary NB-pattern disease who do not receive anti-NTM therapy [2]. Therefore, identifying low sPD-1 as a risk factor for antibiotic initiation in patients with noncavitary NB-pattern NTM-PD has important implications for risk stratification and management. Specifically, patients with low sPD-1 at baseline are at increased risk of rapid progression within 1 year and may benefit from closer monitoring and earlier consideration of therapy [32]. Low plasma sPD-1, low BMI, high smear grade, and cavitary NB pattern are robust predictors of disease progression [32]. A composite score integrating these factors may provide a practical indicator of disease progression and warrants validation in larger studies.

The strengths of this study include its large multicountry cohort design and the standardized definition of antibiotic initiation as a clinically relevant surrogate outcome of disease progression. However, this outcome may be influenced by physician and patient decision-making, local practice patterns, censoring due to loss to follow-up, and potential competing risks, such as death, which were not systematically available across cohorts.

Several limitations should be acknowledged. First, the cohort included both retrospective and prospective components across sites, which may have introduced residual confounding due to cross-country differences in diagnostic workup, follow-up, and treatment thresholds. Nevertheless, the association between sPD-1 and disease progression remained consistent after site-period adjustment, whether sPD-1 was modeled as a continuous or tertile-based variable. However, the tertile cutoffs were derived from the exploratory distribution of sPD-1 levels in our cohort and require further validation. Because all patients in the prospective Japan cohort had follow-up durations shorter than 3 years at the time of analysis, site- and period-adjusted Cox regression analysis for the primary 3-year endpoint was not performed.

Second, detailed radiographic characterization of cavitary lesions, such as size, wall thickness, and anatomical distribution, was not available; such information could refine the phenotypic correlation with sPD-1.

Third, sPD-1 was measured only at baseline; therefore, we were unable to assess dynamic changes over time or in response to treatment. In addition, residual preanalytical variability related to storage duration and sample handling across sites could not be fully excluded despite centralized measurement and standardized protocols.

Fourth, healthy controls were recruited from a single country, whereas patients were enrolled from multiple countries, which may limit comparability of absolute sPD-1 levels between groups.

Fifth, we did not assess key inflammatory markers, such as cytokines, chemokines, C-reactive protein, and albumin, which may have confounded the association between sPD-1 and disease progression.

This study demonstrates that lower baseline sPD-1 levels are associated with both cavitary lesions and increased risk of antibiotic initiation, a clinically relevant surrogate outcome of disease progression, in NB-pattern NTM-PD. These findings support the potential role of sPD-1 as a prognostic biomarker for risk stratification and closer monitoring in this challenging and increasingly prevalent form of NTM-PD. Future studies should validate sPD-1 in broader populations and explore its utility in guiding treatment initiation and monitoring.

All authors contributed to sample and data collection. Drs Pan, Furuuchi, Shu, Morimoto, and Yim performed the data analysis. Drs Pan and Shu drafted the manuscript. Profs Morimoto and Yim critically revised the manuscript. Drs Shu, Morimoto, and Yim are the guarantors of the paper and take responsibility for the integrity of the work as a whole, from inception to publication.

The authors declare that no artificial intelligence–assisted tools were used in the drafting, analysis, or writing of this manuscript.

NCT05678166.

This work includes data that were previously presented in part at the 2024 Annual Congress of the Taiwan Society of Pulmonary and Critical Care Medicine and in part at the 2025 International Conference of the American Thoracic Society.

This study was supported by the APSR – Asia Pacific Society of Respirology – Multi-Society Research Project Fund 2023–2024, Taipei Veterans General Hospital (V113E-006-1, V114E-007-2, V115E-006-2), National Taiwan University Hospital (115-E0007), and the National Science and Technology Council, Taiwan (114-2314-B-075-079).

None declared.

The data supporting the findings of this study are available from the corresponding author upon reasonable request. The data are not publicly available because of privacy or ethical restrictions.