In this study, we analyzed in-hospital mortality using data of more than 16,000 patients with NTM-PD drawn from a nationwide database in Japan. Pulmonary diseases accounted for 68.3% of primary diagnoses during these patients’ hospitalizations. The results of multivariable logistic regression analysis showed that male sex, lower BMI, lower Barthel index score, and hemoptysis were associated with higher in-hospital mortality. Several comorbidities were also associated with higher mortality.
Several previous population-based studies have evaluated risk factors for NTM-related deaths. These studies identified older age [8, 9, 11, 19] and male sex [9,10,11, 19] as potential risk factors for NTM-related deaths. Several comorbid diseases were also shown to be possible risk factors, including chronic obstructive pulmonary disease (COPD) [8, 11], lung cancer [10, 11, 19], bronchial asthma [10], pneumonia [10], and interstitial lung disease [11]. Bloody sputum was also associated with mortality in one single center study [20].
In the present study, we found that most of the participants (50.8%) had comorbid pulmonary infections in addition to NTM. Furthermore, pulmonary infection was significantly associated with in-hospital mortality, whereas, COPD and bronchial asthma were not. It remains unknown why COPD and bronchial asthma were not associated with higher in-hospital mortality. One possibility is that some of the patients hospitalized for exacerbations of COPD or bronchial asthma had better treatment responses.
Almost 90% of NTM-PD in Japan is reportedly MAC-PD [3]. In the present study, 15.2% of the patients received combination therapy including rifampicin, ethambutol, and clarithromycin, which is a standard regimen for MAC-PD, whereas 44.6% did not receive any antibiotics that target NTM. It seems likely that a relatively large proportion of patients in our study required unscheduled hospitalization for management of comorbid diseases or conditions.
In a previous study of 178 patients with NTM-PD from Oregon, USA, regular use of immunosuppressive medication was a risk factor for death [19]. In our study, about one third of patients who received corticosteroids after admission died during hospitalization. It is possible that most of the patients who were treated with corticosteroids had severe comorbidities on admission. Further studies are needed to elucidate the association between regular use of corticosteroids and prognosis of NTM-PD.
This study included BMI data in the multivariable analysis for mortality; to the best of our knowledge, no published studies have examined BMI prior to death in patients with NTM-PD. However, several studies have reported an association between weight loss and development of NTM-PD [12, 13, 21,22,23]. In this study, patients with NTM-PD who required unscheduled hospitalization had remarkably low BMIs, the median being 17.5 kg/m2. Furthermore, lower BMI was strongly associated with higher in-hospital mortality. Our findings are in line with those of other hospital-based studies assessing long-term prognosis of MAC-PD patients in Japan, which have repeatedly shown that a BMI of less than 18.5 kg/m2 is associated with higher mortality [12, 13]. It is possible that most of the patients who died during their hospitalizations had cachexia, which is recognized as a complex metabolic syndrome [24].
Development of more effective anti-mycobacterial drugs may be crucial to preventing progression of NTM-PD. However, such drugs may not completely prevent progression of NTM-PD because some patients are likely to have polyclonal and mixed NTM infections acquired from the environment, as well as reinfection with NTM after treatment [25, 26]. Taken together, exploring host factors (such as the mechanisms by which severe weight loss affects susceptibility to, and progression of, NTM-PD) may be important in improving the prognosis of this disease. In fact, two previous studies have reported a possible role for inappropriately secreted adipokines in the pathogenesis of NTM-PD [27, 28]; however, their results were inconsistent and thus require further investigation.
Several limitations must be acknowledged. First, mild cases of NTM-PD without respiratory complications may have not been recorded by the attending physician; this would have resulted in low sensitivity for the diagnosis of mild cases of NTM-PD. NTM-PD is more likely to be diagnosed when it is has resulted in moderate to severe respiratory symptoms. Second, we may have underestimated the proportion of patients who were receiving combination therapy for MAC-PD because anti-mycobacterial drugs prescribed in the outpatient settings are usually withdrawn on admission in more severe cases. This would have prevented us from accurately evaluating the association between antibacterial therapies for NTM-PD and in-hospital mortality.