**3. Results**

#### *3.1. Study Population*

Between January 2010 and December 2016, 6789 patients underwent lung cancer surgery, and 6503 patients were finally analyzed (Figure 1). Of the 6503 patients, 156 (2.4%) patients had one or more positive results of NTM culture in their respiratory specimens after lung cancer surgery, and 59 (0.9%) patients were confirmed to have progressed to NTM-PD.

The patients were followed up for a median of 4.89 (IQR: 3.31–6.32) years, and the 5-year survival rate was 76.7% (Figure 2A). During the follow-up period after lung cancer surgery, 59 patients developed NTM-PD at a median of 3.41 (IQR: 2.17–5.08) years (Figure 2B). The cumulative incidences were 0.1%, 0.5%, 0.9%, and 2.8% at 1, 3, 5, and 10 years, respectively, and the incidence rate was 1.9 (95% confidence interval [CI]: 1.5–2.5) per 1000 person-years. Including suspicious NTM-PD, 156 patients had NTM-positive

results on their respiratory specimens at a median of 2.79 (IQR: 1.43–4.55) years. The cumulative incidences for NTM-positive results were 0.5%, 1.5%, 2.5%, and 5.9% at 1, 3, 5, and 10 years, respectively, and the incidence rate was 5.1 (95% CI: 4.3–6.0) per 1000 person-years.

**Figure 1.** Flow diagram of the study population. \* NTM culture (+) from respiratory specimens without an identification test for NTM species (*n* = 44), NTM culture (+) from only one sputum sample with an identification test for NTM species (*n* = 7), NTM culture (+) from only one sputum sample without an identification test for NTM species (*n* = 182). † Of these 41 patients, 27 patients were included in "Patients with NTM-PD at the time of lung cancer diagnosis (*n* = 16)" or "Patients with suspicious NTM infection at the time of lung cancer diagnosis (*n* = 11)". ‡ NTM culture (+) from respiratory specimens without an identification test for NTM species (*n* = 68), NTM culture (+) from only one sputum sample with an identification test for NTM species (*n* = 25), NTM culture (+) from at least two sputum samples with only one identification test for NTM species (*n* = 4). NTM, nontuberculous mycobacteria.

**Figure 2.** (**A**) The overall survival rate of the study population and (**B**) the cumulative incidence of NTM-PD and NTM-positive results after lung resection surgery. NTM-PD, nontuberculous mycobacterial pulmonary disease.

#### *3.2. Baseline Characteristics of Patients Who Developed NTM-PD and Were NTM-Positive after Lung Cancer Surgery*

The median age of the study population was 63 years, and 61.2% were male (Table 1). Patients with NTM-PD had a greater distribution of being > 65 years (59.3% vs. 42.7%, *p* = 0.010), having a smoking history (*p* = 0.007), and having a BMI ≤ 18.5 kg/m<sup>2</sup> (10.2% vs. 2.6%, *p* = 0.005). In addition, the proportion of patients with bronchiectasis (18.6% vs. 6.1%, *p* = 0.001) and centrilobular bronchiolitis (13.6% vs. 2.3%, *p* < 0.001) on CT images at the time of the lung cancer diagnosis was higher.

**Table 1.** The baseline characteristics of patients with NSCLC and the development of NTM-PD after lung resection.


Data are presented as n (%) or the median (interquartile range). NSCLC, non-small cell lung cancer; NTM-PD, nontuberculous mycobacterial pulmonary disease; BMI, body mass index; TB, tuberculosis; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus. *\* p* values were calculated with the use of a Mantel–Haenszel test (trend test). † Includes large cell neuroendocrine carcinoma, adenosquamous carcinoma, pleomorphic carcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, epithelial myoepithelial carcinoma, and carcinoid tumor.

Similar trends were observed when the same analysis was performed after dividing patients by their NTM culture results for this cohort (Table S1). In addition to the trends of the characteristics mentioned above, patients who developed NTM-positive results were

more likely to be male (73.7% vs. 60.9%, *p* = 0.001), have a previous history of pulmonary TB (22.4% vs. 10.5%, *p* < 0.001), COPD, or asthma (39.7% vs. 26.7%, *p* < 0.001), and have a higher clinical stage at diagnosis (*p* for trend = 0.001) than those who did not develop the NTM-positive results.

Among the factors associated with lung cancer treatment, patients who developed NTM-PD more commonly received neoadjuvant treatment (20.3% vs. 9.5%, *p* = 0.005) than those who did not (Table 2). In addition, the incidence of PPCs (27.1% vs. 16.8%, *p* = 0.035) was higher in patients with NTM-PD than it was in those without NTM-PD.


**Table 2.** The treatment profile for NSCLC and the development of NTM-PD after lung resection.

Data are presented as n (%). NSCLC, non-small cell lung cancer; NTM-PD, nontuberculous mycobacteria pulmonary disease; CCRT, concurrent chemoradiotherapy; VATS, video-assisted thoracoscopic surgery; PPC, postoperative pulmonary complication. *\* p* values were calculated with the use of a Mantel–Haenszel test (trend test). † Except for 63 patients where no residual tumor appeared in the surgical specimen after neoadjuvant treatment (pathologic complete response [ypCR]). ‡ Pneumothorax and/or prolonged air leak (*n* = 502), respiratory failure that required mechanical ventilation (*n* = 253), pneumonia (*n* = 231), pleural effusion (*n* = 150), others (atelectasis, bronchopleural fistula, pulmonary thromboembolism, etc.) (*n* = 291). Some patients had more than one complication. § Excluded 48 patients due to data unavailability.

Along with these differences, patients with NTM-positive results were also more likely to receive an adjuvant treatment (35.9% vs. 27.9%, *p* = 0.018) than those without NTMpositive results (Table S2). There were no statistical differences in the extent of surgical resection and pathologic stage whether patients developed NTM-PD or not as well as among patients with or without NTM-positive results.

Among the 59 NTM-PD patients, Mycobacterium avium complex (MAC) was the most common pathogen (Table 3). NTM-PD patients with the NB form accounted for 70%, and the NB form with cavity lesions accounted for 20%. In the 97 patients classified with suspicious NTM-PD, the reasons for not satisfying the microbiologic criteria were as follows: NTM culture (+) from respiratory specimens without an identification test for NTM species (*n* = 68), NTM culture (+) from only one sputum sample with an identification test for NTM species (*n* = 25), and NTM culture (+) from at least two sputum samples with only one identification test for NTM species (*n* = 4). In suspicious NTM-PD patients, about 80% of patients had the NB form, and four (4.1%) of them had cavity lesions (Table S3).

**Table 3.** Characteristics of definitive NTM-PD.


Data are presented as *n* (%). NTM-PD, nontuberculous mycobacteria pulmonary disease. \* M. fortuitum complex (*n* = 2), M. kansasii (*n* = 1), M. szulgai (*n* = 1), M. peregrinum (*n* = 1), and M. gordonae (*n* = 1).

#### *3.3. Factors Associated with the Development of NTM-PD and NTM-Positive Results*

The emergence of NTM-PD was independently associated with an age > 65 years (adjusted hazard ratio (aHR): 2.44; 95% CI: 1.43–4.16; *p* = 0.001), a BMI ≤ 18.5 kg/m<sup>2</sup> (aHR: 3.85; 95% CI: 1.62–9.16; *p* = 0.002), ILD (aHR: 8.23; 95% CI: 1.96–34.51; *p* = 0.004), bronchiectasis (aHR: 2.38; 95% CI: 1.16–4.91; *p* = 0.019) or centrilobular bronchiolitis (aHR: 3.91; 95% CI: 1.71–8.93; *p* = 0.001) on CT imaging at the time of lung cancer diagnosis, PPCs (aHR: 1.90; 95% CI: 1.07–3.39; *p* = 0.029), and treatment with both chemotherapy and radiotherapy (aHR: 2.70; 95% CI: 1.42–5.12; *p* = 0.002) (Table 4).

In contrast, the development of NTM-positive (NTM-PD and suspicious NTM-PD) results was not associated with a lower BMI out of the seven variables, while ever-smokers (aHR, 1.48; 95% CI: 1.02–2.13), a history of pulmonary TB (aHR: 2.27; 95% CI: 1.55–3.31; *p* < 0.001), and thoracostomy (aHR: 1.53; 95% CI: 1.07–2.21; *p* = 0.021) were additionally related (Table S4).

**Table 4.** Prognostic factors associated with the development of NTM-PD after lung resection for NSCLC (*n* = 6503).



**Table 4.** *Cont*.

NTM-PD, nontuberculous mycobacteria pulmonary disease; NSCLC, non-small cell lung cancer; HR, hazard ratio; CI, confidential interval; BMI, body mass index; TB, tuberculosis; COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease; CT, computed tomography; VATS, video-assisted thoracoscopic surgery; PPC, postoperative pulmonary complication; CTx, chemotherapy; RTx, radiotherapy. \* Includes large cell neuroendocrine carcinoma, adenosquamous carcinoma, pleomorphic carcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, epithelial myoepithelial carcinoma, and carcinoid tumor. † Pneumothorax and/or prolonged air leak (*n* = 502), respiratory failure that required mechanical ventilation (*n* = 253), pneumonia (*n* = 231), pleural effusion (*n* = 150), others (atelectasis, bronchopleural fistula, pulmonary thromboembolism, etc.) (*n* = 291). Some patients had more than one complication.
