This retrospective study revealed that detection of the MAC-Ab was a significant risk factor for hemoptysis among patients with MAC pulmonary disease. The significant positive trends were also observed in the association of the MAC-Ab titer with the prevalence of hemoptysis. As with the species-specific analyses, neither the sensitivity analyses among patients with no anticoagulant / antiplatelet agents nor those among the patients with no NTM treatment altered the results substantially. This is the first study to evaluate the influence of disease activity, based on the MAC-Ab, on hemoptysis in NTM patients.
Hemoptysis is well known to be progressively more prevalent with advancing NTM lung disease [11]. Since the MAC-Ab titer is reported to reflect disease activity [12, 13], it is considered to be a biomarker for disease progression and, as a consequence, hemoptysis. Since hemoptysis is one of the most principal factors leading physicians to initiate NTM treatment [11, 17], measuring the MAC-Ab may contribute not only to the early detection of high-risk patients for hemoptysis but also to early intervention in NTM and, as a result, to the prevention of hemoptysis in MAC patients.
To date, there has been only one study investigating risk factors for hemoptysis in subjects with NTM lung disease that mentioned that there was no significant biomarker for hemoptysis except for being young [3]. The inverse association between age and hemoptysis was assumed to be due to age-related decline in immune responses [3, 18]; the negative impact of age might have been by virtue of an interaction with immune activation against NTM pathogens. Meanwhile, with regard to tuberculosis, the effects of age on hemoptysis are controversial [18–20]. In the present study, testing positive for the MAC-Ab was significantly related to an increase in the prevalence of hemoptysis, while being young was not; the MAC-Ab seemed to be a more valuable marker for the progression of MAC disease and hemoptysis than age. As for the impact of age on hemoptysis, further research is warranted.
Regarding MAC species, both the frequency of hemoptysis and the impact of the MAC-Ab on hemoptysis were equivalent between subjects with detected M. avium and M. intracellulare in this study. The former findings were in line with previous research [3, 21]. Moreover, there was no evidence of differences in MAC-Ab levels between subjects with M. avium and those with M. intracellulare [12, 13]. This suggests that, in patients with MAC lung disease, the MAC-Ab is a universal risk factor for hemoptysis even in the population with a different distribution of MAC species from ours.
The strengths of our study were the highly accurate diagnosis of NTM based on the ATS/IDSA criteria and the exclusion of cases with coexisting pulmonary tuberculosis or aspergillosis to minimize factors perturbing the relationship between the MAC-Ab and hemoptysis. However, some potential limitations should be noted. First, the MAC-Ab levels were based on a single measurement. This may cause misclassification of the MAC-Ab level, which could have weakened the association found in the present study, biasing the results toward a null hypothesis. Second, there was the possibility of an increase in the risk of hemoptysis due to anticoagulant/antiplatelet use. However, there was no significant difference in the frequency of such medication use between the seropositive and seronegative groups. Additionally, the sensitivity analyses excluding subjects with such medication showed similar results. Thus, this potential bias did not appear to have affected the present results. Third, antibiotic treatment might have reduced the risk of hemoptysis in a part of the study population and consequently weakened the results. In our study, the proportion of subjects with NTM treatment was, to some extent, higher in the seropositive group than in the seronegative one; the positive association of the MAC-Ab with hemoptysis might have been underestimated. However, similar findings were observed in the analyses including only patients with no NTM treatment. Therefore, this limitation may not have altered our conclusions. Lastly, the present outcomes might lack external validity and generalizability owing to the study design as single-center analyses. However, the prevalence of hemoptysis in the present study was in accord with previous epidemiological evidence (about one-third of NTM patients) [1–4]. Furthermore, as mentioned above, the results were consistent across MAC species; we speculate that it is reasonable to extrapolate the current findings to the general population with MAC infection. To overcome the aforementioned limitations and verify the present results, planning for a multicenter prospective cohort study is underway.