Pulmonary MAC disease is common in middle-aged and elderly women who are lean (23). Similar patient characteristics were observed in this study, suggesting that low BMI is an aggravating factor for pulmonary MAC. Previous reports have shown that BMI was significantly lower in the exacerbation group of pulmonary MAC disease than in the stable group (24), and that low BMI is a risk factor for mortality (25). Lean muscles with reduced respiratory and reduced expiratory forces can lead to air trapping, chronic inflammation may result in hyponutrition and weight loss, whereas bacterial colonization may persist and worsen because of decreased drainage of the peripheral airways (26).
The present study also suggested that patients with pulmonary MAC disease have high levels of anxiety and mild depression. Additionally, symptoms of depression have been observed in a high proportion of patients with pulmonary NTM disease (2).
JST is a combination of Shoyusang’s components (Japanese angelica root, peony root, atractylodes rhizome, poria sclerotium, Mentha herb, bupleurum root, and glycyrrhiza), which are effective for treating irritability and malaise, and citrus unshiu peel and cyperus rhizome, which are effective for treating depression. Additionally, it contains herbal medicines with moisturizing, heat-clearing, and expectorant-tussive effects, such as ophiopogon tuber, fritillaria bulb, lycium bark, and anemarrhena rhizome. JST is used in the treatment of prolonged respiratory illnesses that cause cough, phlegm, and slight fever. It also calms the autonomic nervous system and cures the irritability and nervousness caused by mental stress (27). Glycyrrhiza, lycium bark, and citrus unshiu peel have antidepressant and anxiolytic effects. Atractylodes rhizome, poria sclerotium, bupleurum root, glycyrrhiza, ophiopogon tuber, fritillaria bulb, citrus unshiu peel, and cyperus rhizome have anti-inflammatory effects (28–34). Additionally, bupleurum root, glycyrrhiza (35), and anemarrhena rhizome (36) have anti-allergic effects, whereas glycyrrhiza and Mentha herb have antibacterial and antifungal effects, respectively (37,38). Peony root has anti-inflammatory, anti-allergic, fibrosis-inhibiting, and apoptosis-inhibiting effects (39,40). Atractylodes rhizome and glycyrrhiza have immunomodulating effects (41,42).
We hypothesized that JST administration would improve respiratory symptoms, weight loss, immune function, and psychiatric symptoms in patients with pulmonary MAC disease. The primary endpoints were the CAT score, body weight, and NK cell activity after 3 months. The results showed that there were no significant changes in these endpoints after 3 months. However, the SDS score showed a significant improvement, proving that JST improves depression.
The exacerbation group showed only slight improvement in the SDS score with JST, whereas the non-exacerbation group showed significant improvement. According to the evaluation of STAI, both state anxiety and trait anxiety were increased, up to above the normal adult levels before drug administration; however, there was no difference between the exacerbation and non-exacerbation groups. There is a strong correlation between the parameters of STAI and SDS (43), but this study showed a discrepancy between them. The STAI is an anxiety test that was standardized in Japan by Mizuguchi et al. and developed by Spielberker et al. based on the trait and state model of anxiety theory (13). The STAI consists of two scales: state anxiety, which represents the degree of anxiety at the time of the current transient measurement, and trait anxiety, which represents the tendency toward anxiety as a personality trait. The SDS, however, is a psychological test consisting of 20 questions that was developed by Zung in 1965 (12). It assumes the absence of physical illness and incorporates physical symptoms, such as weight loss and anorexia, as indicators of depression. In the present study, the non-exacerbation group did not gain any weight after JST treatment, and it is unlikely that the improvement in clinical symptoms alone had an effect. Additionally, lymphocytes and albumin significantly decreased in the exacerbation group over the course of the study. These decreases may have been suppressed in the non-exacerbation group. However, the fact that the SDS score improved rather than remained unchanged suggests that there may be additional factors involved that determine the presence of depression apart from weight parameters alone. Therefore, JST was considered to be effective.
In the non-exacerbation group, NK cell activity showed an increasing trend before and after JST administration. Though a complementary rise in NK cell activity occurs with the administration of Chinese medicine (4). In contrast, in this study, NK cell activity did not increase in all the patients that were administered JST; it only increased in the non-exacerbation group. NK cell activity reportedly decreases in patients with mood disorders (major depression and bipolar disorder) (44). In the present study, in the non-exacerbation group, NK cell activity improved and the SDS score improved significantly. IL-18 enhances Th1 cell activation and NK cell activity (45), and we investigated the relationship between IL-18 and Th1 cell activation in the exacerbation group. IL-18 increased in the exacerbation group before and after JST treatment, and it was higher in the non-exacerbation group after treatment. Although this may be related to the Th1 cell predominance of pulmonary MAC disease, it was not related to NK cell activity. Furthermore, in this study, NK cell activity increased in the non-exacerbation group after JST treatment, suggesting that the cause of the increase may not be explained entirely by the increase in IL-18. Further studies are required to elucidate the mechanism of pulmonary MAC disease.
In this study, the antidepressant effect of JST and the improvement in respiratory symptoms were observed in the non-exacerbation group. Therefore, in our humble opinion, we believe that it is important to identify the non-exacerbation group at the time of the initial diagnosis and to administer JST. The non-exacerbation group had higher BMI and lower CT scores than the exacerbation group before JST administration. A receiver-operating characteristic curve was created, the cutoff value for BMI was 19.2, sensitivity was 72.7%, and specificity was 80.0%. Although there was no significant difference in the CT values, the cutoff value for the CT score was 6.5, sensitivity was 80.0%, and specificity was 63.6%.
Additionally, nutritional indices, such as lymphocytes, albumin, cholinesterase, and the CONUT score, worsened before and after JST treatment. Because all groups received JST, it could not be determined whether the worsening was caused by JST treatment or the disease itself. The overall trend of worsening TNF-α and the significant worsening of TNF-α in the exacerbation group suggest that inflammation worsened as the disease progressed. However, despite the exacerbation of inflammation and nutrition, the CAT score improved in the non-exacerbation group, directly suggesting an improvement in the respiratory symptoms, which is another effect of JST confirmed by this study.
CCL17, also known as TARC, is a member of the CC chemokine family that is highly expressed in the thymus and other cells, including keratinocytes, endothelial cells, dendritic cells, bronchial epithelial cells, and fibroblasts (46). CCL17/TARC has an important role in T-cell development, mature T-cell trafficking, and activation in the thymus (47). Reduced serum CCL17/TARC levels have been suggested to be a predictor of severe disease in patients with the novel coronavirus disease (48). In the present study, CCL17/TARC was decreased in the non-exacerbation group treated with JST. CCL17/TARC is mainly produced and induced by the Th2 cytokines. The fact that CCL17/TARC decreased with time suggests that the influence of Th2 is reduced in the non-exacerbation group. In the present study, CCL17/TARC was not significantly different in the exacerbation group, but it was significantly decreased in the non-exacerbation group, suggesting that the influence of Th2 is more strongly reduced in the non-exacerbation group. However, IL-18, which activates the Th1 cells, increased in the exacerbation group after JST treatment and was higher than that in the non-exacerbation group, suggesting that the Th1/Th2 balance may be slightly different in the exacerbation and non-exacerbation groups with pulmonary MAC disease. Because the aforementioned effects could not be determined by this study alone, further investigation is needed. Furthermore, whether JST treatment affected the CCL17/TARC results could not be determined through the results of this study alone.
Despite the evaluation of a large number of findings, this study had some limitations. There were only 24 patients in this study, and the sample sizes of the non-exacerbation and exacerbation groups were small; therefore, statistical analyses were unable to reveal medically significant differences. Additionally, a multivariate analysis of the non-exacerbation group could not be performed because of the small number of patients. This was a single-center study, and the number of patients that could be enrolled during the study period was limited. In addition, it was not possible to estimate whether patients would be placed in the exacerbation or non-exacerbation group; therefore, it was difficult to set a target number of patients for each group in advance. Furthermore, as this study was not a double-blind, comparative study, it did not include a control group given a placebo drug. Furthermore, it did not include blinding of the participants for placement in treatment or placebo groups either. Unfortunately, it was not feasible to obtain a suitable placebo medication at this time, because the effects of JST on MAC are hitherto unknown. Therefore, it is unclear whether the worsening of the nutritional status and inflammation are natural consequences of the progression of pulmonary MAC disease or the effects of JST. Double-blind, comparative studies should be conducted in the future to further investigate the effects of JST. We therefore consider this as a preliminary study, to be followed by double-blind, comparative studies that will be conducted later.
The most recent guidelines suggest that the mild disease group should be treated aggressively. We initially considered an evaluation of two groups—standard treatment group and standard treatment plus Chinese herbal medicine group—for our study design. However, we feared that it would not be possible to examine whether the changes in the findings were attributable to the effects of JST; therefore, we chose a different study design. In actual clinical practice, many patients with very mild cases of MAC are merely observed and do not receive any treatment; however, this study demonstrated the effects of JST on MAC patients at that stage. In addition, while many patients with pulmonary MAC are under observation without exacerbation, there are patients with exacerbation who require treatment. In this context, it is clinically meaningful to estimate exacerbation factors by comparing the exacerbation group with the non-exacerbation group, and to pre-emptively identify those who are likely to have an exacerbation.