Six hundred eighty-one patients were included in this study (Supplementary Figure S1). Most of the patients were female (56.2%), with a median age of 66.0 (interquartile range [IQR], 56.7–73.2) years and a BMI of 21.1 (IQR, 19.2–23.1) kg/m2. The most prevalent comorbidity was a history of tuberculosis (31.1%), followed by hypertension (24.4%), malignancy (17.3%), and diabetes mellitus (13.2%). Most of the patients had a mild-to-moderate severity of NTM-PD; 97 (14.2%), 189 (27.7%), 192 (28.2%), 143 (21.0%), 47 (6.9%), and 13 (1.9%) patients had BACES scores of 0, 1, 2, 3, 4, and 5, respectively (Supplementary Figure S2).
Patients with severe NTM-PD were more likely to have a smoking history (51.6%) than those with mild (11.2%) and moderate NTM-PD (34.1%) (p < 0.001 by chi-square test). A history of tuberculosis and chronic pulmonary comorbidities, such as chronic obstructive pulmonary disease, asthma, and idiopathic pulmonary fibrosis, were more common in patients with severe NTM-PD than in others. Compared to patients with moderate (71.6%) and mild (61.9%) NTM-PD, patients with severe NTM-PD were more likely to be diagnosed using two repetitive sputum cultures (83.3%) rather than invasive methods (p = 0.001 by chi-square test). Patients with severe NTM-PD also had a higher initial sputum smear positivity rate (36.7% vs. 10.5% vs. 6.6%, p < 0.001 by chi-square test) (Table 1).
Patient symptoms and NTM species
Common symptoms were cough (36.0%), sputum (29.1%), hemoptysis (18.2%), and dyspnea (13.8%). Patients with severe NTM-PD were more likely to have dyspnea (26.7%) than those with mild (8.4%) and moderate (16.1%) NTM-PD (p < 0.001 by chi-square test). Symptoms of body weight loss (6.7% vs. 3.0% vs. 1.0%, p = 0.029 by chi-square test) and anorexia (3.3% vs. 0.3% vs. 0.0%, p = 0.002 by chi-square test) were also more common in patients with higher BACES scores (Supplementary Table S2).
MAC was the prevalent causative species (68.8%), followed by MABC (14.5%) and Mycobacterium kansasii (2.5%). Fifty-five (8.1%) patients were diagnosed with mixed infections. Patients with higher BACES scores had were more likely to have M. intracellulare and M. abscessus infections. In contrast, those with lower BACES scores were more likely to have M. avium and M. massiliense infections (p = 0.008 by chi-square test) (Supplementary Table S3).
Disease progression and treatment response
Of the 681 patients, 333 (48.9%) had progressive disease. The median time to progression was 2.6 (IQR, 1.2–10.5) months, which was shorter for patients with severe NTM-PD (median, 1.3 months) than for those with moderate (2.5 months) or mild (3.8 months) NTM-PD (p < 0.001). Compared to patients with mild NTM-PD, patients with moderate (HR, 1.66; 95% confidence interval [CI], 1.31–2.11) or severe (HR, 2.76; 95% CI, 1.91–3.99) NTM-PD had a higher risk of disease progression (log-rank test with Bonferroni correction p < 0.001) (Table 2 and Fig. 1a). Of the five components of the BACES score, the presence of any cavity (HR, 2.25; 95% CI, 1.77–2.88), low BMI (HR, 1.76; 95% CI, 1.35–2.30), elevated ESR (HR, 1.59; 95% CI, 1.27–1.98), and male sex (HR, 1.27; 95% CI, 1.02–1.58) were associated with the risk of disease progression. Elderly age (≥ 65 years) was not significantly associated with disease progression (HR, 1.05; 95% CI, 0.85–1.31).
Of the 333 patients with progressive disease, 256 had at least three sputum cultures after treatment. Of the 256 patients, 142 (55.5%) had culture conversion. The culture conversion rate was 65.5% in mild NTM-PD, 52.4% in moderate NTM-PD, and 40.7% in severe NTM-PD (p = 0.042 by chi-square test). However, the time to culture conversion did not reveal a significant difference between the groups (log-rank test with Bonferroni correction p = 0.596) (Table 2 and Fig. 1b).
As of December 31, 2020, 209/681 (30.7%) patients had died after a median of 8.6 (IQR, 5.4–10.9) years following NTM-PD diagnosis. Compared to the mild group, the moderate (HR, 7.44; 95% CI, 4.74–11.67) and severe (HR 26.05, 95% CI 15.60–43.50) groups had higher risks of all-cause mortality in this separate cohort (log-rank test with Bonferroni correction p < 0.001) (Table 2 and Fig. 1c). The estimated survival rates and actual survival rates showed a good correlation (Supplementary Figure S3). Elderly age (HR, 6.51; 95% CI, 4.48–9.45), elevated ESR (HR, 3.54; 95% CI, 2.60–4.84), male sex (HR, 3.36; 95% CI, 2.52–4.48), lower BMI (HR, 2.33; 95% CI, 1.71–3.18), and presence of cavity (HR, 1.78; 95% CI, 1.31–2.42) were all associated with the time to all-cause mortality. Using the Kaplan–Meier estimator, the estimated probability of 5-year mortality from our observed data was as follows: BACES 0 (2.8%), BACES 1 (6.5%), BACES 2 (22.7%), BACES 3 (47.4%), BACES 4 (73.7%), and BACES 5 (91.0%).
Of 209 patients, 94 died of respiratory causes or infections. Details of the causes of death are presented in Supplementary Table S4. Patients with negative culture conversion had a lower mortality risk due to respiratory causes or infection (log-rank p = 0.038) (Fig. 2). Compared to the mild group, the moderate (HR, 7.80; 95% CI, 3.87–15.73) and severe (HR, 31.97; 95% CI, 14.73–69.42) groups had significantly higher risks of mortality from respiratory causes or infection (log-rank p < 0.001) (Table 2 and Fig. 1d). Elderly age (HR, 5.86; 95% CI, 3.42–10.05), elevated ESR (HR, 4.59; 95% CI 2.80–7.54), lower BMI (HR, 3.65; 95% CI, 2.39–5.58), male sex (HR, 2.36; 95% CI, 1.56–3.56), and the presence of a cavity (HR, 2.20; 95% CI, 1.42–3.41) were all associated with mortality from respiratory causes or infection.
Because the BACES score does not include underlying comorbidities, we performed a multivariate analysis including the underlying comorbidities. Compared to mild NTM-PD, moderate (adjusted HR, 5.13; 95% CI, 2.48–10.59) and severe (adjusted HR, 18.29; 95% CI, 7.92–42.20) NTM-PD were independently associated with the risk of mortality from respiratory causes or infection. Among the comorbidities, chronic liver disease (adjusted HR, 3.82; 95% CI, 1.23–11.90), tuberculosis (adjusted HR, 1.61; 95% CI, 1.05–2.47), chronic obstructive pulmonary disease (adjusted HR, 1.61; 95% CI, 1.75–4.64), and idiopathic pulmonary fibrosis (adjusted HR, 13.77; 95% CI, 6.26–30.31) were also independently associated with a higher risk (Table 3).