Patients characteristics
During the study period, 1,317 patients were newly diagnosed with NTM-PD. The final analysis included 1,165 cases, with 139 cases excluded because of non-MAC-PD (Fig. 1). The mean age was 70.7 years, and 371 (31.8%) were male. M. avium and M. intracellulare were detected in 517 (44.4%) and 648 (55.6%) patients, respectively (Table 1). Within 5 years, 656 (56.3%) patients received treatment for MAC-PD. During the observation period, all-cause mortality occurred in 183 patients (15.7%), and respiratory infection-related mortality occurred in 67 patients (5.8%). In total, 932 and 233 patients were randomly allocated to the derivation and validation groups, respectively.
Flowchart of study patients. JSTNM, Japanese Society for Tuberculosis and Nontuberculous Mycobacteriosis; MAC, Mycobacterium avium-intracellulare complex; NTM-PD, nontuberculous mycobacterial pulmonary disease.
Risk factors for mortality
To identify the risk factors for respiratory infection-related mortality in MAC-PD, we evaluated the backgrounds, comorbidities, and laboratory findings at diagnosis of 932 patients in the derivation group. Univariate analysis revealed that age ≥ 65 years, male sex, BMI < 18.5, interstitial pneumonia (IP), chronic obstructive pulmonary disease (COPD), bronchial asthma, oral corticosteroid (OCS) use, inhaled corticosteroid use (ICS), Alb < 3.5 g/dL, elevated ESR (> 15 mm/h in male and 20 mm/h in female), lymphocyte count < 1,000/µL, M. intracellulare, cavity formation, and cavitary nodular bronchiectatic pattern were associated with an increased mortality risk (Table 2). Cox proportional hazards analysis was performed using the following variables: age ≥ 65 years, male sex, IP, COPD, ICS use, Alb < 3.5 g/dL, and cavitary lesions ≥ 2 cm in diameter (Table 2). Multicollinearity among these variables was assessed using the VIF, and all variables had VIF values below 3, indicating negligible multicollinearity. ESR was excluded because of missing data for 563 patients (60.4%). The results indicated that age ≥ 65 years, male sex, IP, Alb < 3.5 g/dL, and cavitary lesions ≥ 2 cm in diameter were independent risk factors for respiratory-infection related mortality (Table 2).
Overall, respiratory infection-related death occurred in 32 males (11.0%) and 19 females (3.0%). Male had a significantly higher respiratory infection-related mortality rate than female, as assessed by the log-rank test, with a crude hazard ratio of 5.12 (95% confidence interval [CI]: 2.63–9.99) (Fig. 2a). Age ≥ 65 years was significantly associated with respiratory infection-related mortality (HR 4.02, 95% CI: 2.18–7.44; Fig. 2b), as was IP (HR 5.32, 95% CI: 1.18–24.1; Fig. 2c). Hypoalbuminemia (Alb < 3.5 g/dL) demonstrated the strongest association (HR 8.69, 95% CI: 3.69–20.5; Fig. 2d), while cavitary lesions ≥ 2 cm in diameter were also significantly associated (HR 4.20, 95% CI: 1.56–11.3; Fig. 2e).
Kaplan–Meier analyses of patients in the derivation group. Male sex (a), age over 65 years (b), IP (c), hypoalbuminemia (d), and cavity formation (e) were associated with a significantly poorer prognosis. Without cavity ≥ 2 cm includes patients with no cavity or cavities < 2 cm. Cases with missing data were excluded from the analysis. IP, interstitial pneumonia.
Throughout the study, 33 patients (3.5%) in the derivation group and 6 patients (2.6%) in the validation group had coinfection with chronic pulmonary aspergillosis (CPA), either at diagnosis or during follow-up (Table 1). In a univariate analysis of respiratory infection-related mortality, the development of CPA was significantly associated with mortality, with a crude HR of 6.64 (95% CI: 3.0–13.0). Because CPA typically developed after the diagnosis of NTM-PD, it was not included as a variable in the Cox proportional hazards analysis.
Construction of the prognostic scoring model
We included 5 independent risk factors identified through multivariate analysis to develop a prognostic scoring model. Based on the adjusted hazard ratios from the Cox proportional hazards model in the derivation group, we developed a scoring system (MAC prognostic score) by assigning 2 points to Alb < 3.5 g/dL, and 1 point each to age ≥ 65 years, male sex, IP, and cavitary lesions ≥ 2 cm in diameter.
Among the 795 patients in the derivation group without missing scoring data, the area under the ROC curve (AUC) for the MAC prognostic score was 0.86 (Fig. 3a). To determine the optimal prognostic cutoff value for respiratory infection-related mortality within 5 years, we calculated the Youden index (sensitivity + specificity − 1) based on the ROC curve. A score of ≥ 3 yielded the highest index. At this cutoff, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio, and negative likelihood ratio were 81.8%, 74.7%, 12.3%, 99.0%, 3.23, and 0.14, respectively. The treatment induction rates within 5 years of diagnosis were 75.0% (96/128) for score 0, 54.3% (242/447) for scores 1–2, 53.4% (99/185) for scores 3–4, and 62.9% (22/35) for scores 5–6. The Kaplan–Meier curves for the MAC prognostic score demonstrated significantly different prognoses for each score (Fig. 3b). The 5-year respiratory infection-related mortality rates were 0.0% (0/128) for score 0, 1.3% (6/447) for scores 1–2, 8.1% (15/185) for scores 3–4, and 34.3% (12/35) for scores 5–6. A higher score was associated with a poorer prognosis.
Receiver operating characteristic curve for MAC score and Kaplan–Meier analysis in the derivation group. (a) ROC curve of MAC score in the derivation group (n = 795). Cases with missing data were excluded from the analysis. The AUC was 0.86. The sensitivity and specificity were 81.8 and 74.7%, respectively, at a cutoff value of 3. (b) Kaplan–Meier analysis stratified by MAC score in the derivation group. MAC scores exceeding 3 points showed poor survival outcomes. AUC, area under the curve; ROC, receiver operating characteristic.
Validation of the MAC prognostic score
The MAC prognostic score was subsequently adapted for the validation group and evaluated. Figure 4a shows the ROC curve based on 196 patients without missing scoring data, with an AUC of 0.81. At a cutoff value of 3 points, the sensitivity, specificity, PPV, and NPV for respiratory infection-related mortality within 5 years were 76.9%, 73.8%, 17.2%, and 97.8%, respectively. The treatment induction rates within 5 years of diagnosis were 76.5% (26/34) for score 0, 54.8% (57/104) for scores 1–2, 47.8% (22/46) for scores 3–4, and 66.7% (8/12) for scores 5–6. The Kaplan–Meier curves also demonstrated different prognoses for each score in the validation group (Fig. 4b). The 5-year respiratory infection-related mortality rates were 0.0% (0/34) for score 0, 2.9% (3/104) for scores 1–2, 8.7% (4/46) for scores 3–4, and 25.0% (3/12) for scores 5–6. In the validation group, scores of 3 or higher were associated with a significantly worse prognosis compared to scores below 3.
Receiver operating characteristic curve for MAC score and Kaplan–Meier analysis in the validation group. (a) ROC curve of MAC score in the validation group (n = 196). Cases with missing data were excluded from the analysis. The AUC was 0.81. The sensitivity and specificity were 76.9 and 73.8%, respectively, at a cutoff value of 3. (b) Kaplan–Meier analysis stratified by MAC score in the validation group. MAC scores exceeding 3 points showed poor survival outcomes. AUC, area under the curve; ROC, receiver operating characteristic.
Comparison with the BACES score
The MAC prognostic scores were compared with the BACES scores. A total of 373 patients were included in the analysis, after excluding the cases lacking BMI data195 (16.7%), ESR data 698 (59.9%), or Alb data 173 (14.8%). The AUCs of the MAC prognostic score and BACES score were 0.82 and 0.88, respectively, with no statistically significant differences (Fig. 5a). The Kaplan–Meier curves for the MAC prognostic score and BACES score are presented (Figs. 5b, c). Compared with the BACES score, the MAC prognostic score demonstrated a non-inferior ability to identify the poor prognosis group.
Comparison of MAC and BACES scores. (a) ROC curves of MAC and BACES scores in the population without data loss (n = 373). The AUCs of the MAC and BACES scores were 0.82 and 0.88, respectively, with no significant differences. Kaplan–Meier curves for (b) the MAC score and (c) the BACES score showed comparable prognostic discrimination. AUC, area under the curve; ROC, receiver operating characteristic.
