Clinical characteristics of patients with bronchiectasis with nontuberculous mycobacterial disease in Mainland China: a single center cross-sectional study

Bronchiectasis of noncystic fibrosis origin or noncystic fibrosis bronchiectasis is a chronic structural lung disease characterized by recurrent episodes of lung infection [1]. The colonization and infection of different pathogenic microorganisms can promote the formation of bronchiectasis and affect its severity and prognosis [2, 3]. Bronchiectasis accompanied with positive isolation of Pseudomonas aeruginosa has been associated with worsening lung function, increased frequencies of acute exacerbations, and poor prognosis [1, 4‐6]. The isolation rate of viruses and new bacteria in the sputum of patients with acute exacerbation of bronchiectasis has also significantly increased [7]. Detection of Aspergillus fumigatus in the airways of patients with bronchiectasis is associated with risks for severe disease, worse lung function, and acute exacerbations [8]. Over the past 10 years, the issue of whether the nontuberculous mycobacterium (NTM) pulmonary disease was hospital-acquired or community-acquired had been an interesting research question in the clinical investigations of patients with bronchiectasis [9‐13].

NTM, mycobacteria other than the Mycobacterium tuberculosis complex, and M. leprae, are widely distributed in natural environments. More than 190 species of NTM have been discovered, of which only a few are pathogenic and conditional pathogens [14]. The human infection of NTM was first reported among immunocompromised patients such as those infected with the human immunodeficiency virus (HIV) [15, 16]. The identified risk factors for NTM infection include structural lung disease, lung cancer, receiving immunosuppressive therapy, organ transplantation, HIV infection, and old age [16, 17]. The 5-year all-cause mortality of NTM pulmonary diseases is 10–45%, which is primarily caused by comorbidities, as the mortality related to NTM pulmonary disease is relatively low [17]. Currently, the prevalence rate of NTM pulmonary disease is uncertain, and studies have reported an obvious regional difference, although the prevalence rate has been increasing globally in recent years [18, 19]. In countries with a high burden of tuberculosis, the isolation rate of NTM has significantly increased in recent years [20‐22]. Although the exact impact of NTM pulmonary disease on chronic lung disease remains unclear, patients with chronic obstructive pulmonary disease were found to have a greater risk for worsening situation and high mortality if they were NTM-positive [23, 24]. Patients with bronchiectasis accompanied with a positive result for the Mycobacterium avium complex (MAC) have a higher risk for death [9].

The relationship between bronchiectasis and NTM pulmonary infection is complicated. It is well known that NTM infection can cause bronchiectasis. In recent years, accumulating evidence has confirmed that NTM infection can cause severe bronchiectasis [25‐27]. However, NTM pulmonary disease can present as nodular bronchiectasis on computed tomography (CT), which leads to a misdiagnosis of bronchiectasis with bacterial infection. The prevalence of NTM infection in patients with bronchiectasis is unclear. Previous studies have reported that the positive isolation rate of NTM in patients with bronchiectasis is 1.7–30% [9, 25], whereas the rate is up to 54% in US [28]. The diagnosis and treatment of NTM pulmonary disease still remain challenging issues in clinical practice. Recent guidelines recommend that the diagnosis of NTM pulmonary disease must be based on clinical manifestations and imaging and microbiological results [14]. However, patients with bronchiectasis always have respiratory symptoms during stable and acute exacerbations, and chest CT can also show nodules, bronchiectasis, and cavities caused by other pathogenic infections, causing difficulty in diagnosing NTM pulmonary disease in these patients. A positive result of NTM does not guarantee the diagnosis of the disease, and the diagnosis of NTM pulmonary disease is often delayed because the symptoms are mild and the excretion of NTM in the sputum is intermittent with few colonies retrievable in culture [17]. Furthermore, the proportions of misdiagnosis and inappropriate treatment of NTM are largely unknown [29]. However, there exists limited evidence in this regard, and especially, there are still no data from Mainland China to evaluate the clinical characteristics and other related characteristics among patients with bronchiectasis and NTM.

Therefore, we conducted this cross-sectional study to evaluate the prevalence, clinical characteristics, and treatment status of patients with NTM pulmonary disease, to evaluate their clinically predictive significance, and to provide evidence for the management of bronchiectasis with NTM pulmonary disease.

This study was conducted on 202 patients with bronchiectasis from 19 provinces of China. Most patients had mild disease according to the FACED score, with a course of bronchiectasis of < 10 years. In total, 23.3% of patients were diagnosed with NTM pulmonary disease, and the M. avium—intracellular complex and M. abscessus branch complex were the primary pathogens isolated from their specimens. Unlike the majority of previous studies [9, 33‐35] where only once-positive result of sputum specimen was used for NTM diagnosis, in the present study, all the 47 patients with NTM pulmonary disease fulfilled the criteria of NTM pulmonary disease and were diagnosed with NTM pulmonary infection based on progressive or new abnormal images in HRCT, and 72.3% of them were started on the standard treatment of anti-NTM within 3 months after diagnosis. Most clinical characteristics of patients with bronchiectasis with NTM pulmonary disease and those of patients without NTM pulmonary disease were similar. The multiple regression analysis revealed that HRCT imaging characteristics comprised the major difference between those with NTM pulmonary disease and without NTM pulmonary disease.

The HRCT manifestations of patients with NTM pulmonary disease and normal immune are generally divided into the following three types: fibrocavitary lesions, nodular bronchiectasis and hypersensitivity pneumonia [36]. Our study demonstrated that all patients with NTM pulmonary disease have the imaging characteristics of “nodular bronchiectasis” on HRCT, irrespective of the type of NTM, accompanied with tree-in-bud sign, consolidation shadow, infiltration shadow, and cavity. Similarly, a retrospective study reviewed the HRCT images of 29 patients with a positive bronchial wash culture result and found that the presence of bronchiectasis, cavitary nodules with feeding bronchus sign, and tree-in-bud nodules in the middle lobe and lingula are suggestive of NTM infection [37]. This central lobular nodule may indicate the spread of NTM infection along the bronchus [38]. We observed that 72.3% of patients with bronchiectasis and NTM pulmonary disease had nonlobular central nodules on HRCT. Another study [39] evaluated the thoracic HRCT images of 63 patients with NTM infection and reported that 81% had nodules, 39.8% had lobular centrality, 11.6% had peripheral lymphatics, 9.5% had random distribution, and 20.6% had mixed. NTM are less pathogenic than tuberculous bacteria; hence, compared with tuberculosis, NTM pulmonary disease has fewer cavities [40] and thinner wall [36]. In our study, 29.8% of NTM cases had cavitation on HRCT, which was significantly higher than that in patients with non-NTM pulmonary disease (5.8%). In patients with bronchiectasis combined with NTM pulmonary disease, the lesions were primarily located in the middle or lingual lobe and were independently related to the NTM pulmonary disease. However, in patients without NTM pulmonary disease, the lesions were primarily located in the lower lobe. These results were consistent with previous findings [28]. Although imaging characteristics can be used to distinguish NTM infection from bronchiectasis caused by common bacterial infections and are helpful for the early diagnosis of NTM infection, the major concern is the lack of specificity. Lung infections caused by other pathogens, such as fungal infection, might present similar radiological findings. We thought the dynamic changes of images and the typical image characteristics of NTM pulmonary disease might help physician to clinically diagnose NTM pulmonary disease. Nevertheless, it is necessary to evaluate and incorporate clinical systemic inflammatory responses and microbial testing to aid in the differential diagnosis.

Unlike tuberculosis, NTM pulmonary infection does not induce specific clinical symptoms in hosts with normal immunity [41]. Consistent with previous studies [28, 42], our study demonstrated that patients with bronchiectasis and NTM pulmonary infection rarely have fever. We did not detect a significant difference in the culture positive rate of P. aeruginosa, the course of bronchiectasis, the severity of bronchiectasis, and lung function FEV1% in patients with and without NTM pulmonary disease, which is consistent with previous studies [11, 34]. The study of Sulaiman [43] elucidated the difference in the sputum microbiome between patients with bronchiectasis with or without NTM pulmonary disease, which might support that there is a lack of special clinical characteristics in these patients with NTM pulmonary disease. Studies have reported that NTM pulmonary disease is more likely to occur among low-weight postmenopausal women [16, 33, 44], and our study also suggested that patients with bronchiectasis and NTM pulmonary disease tended to be of low weight and older aged women, as 74.5% cases of NTM pulmonary disease were diagnosed at the age of > 50 years. Compared with patients without NTM, a greater number of patients with NTM pulmonary disease frequently had acute exacerbations in the past year, which is different from previous studies. A study conducted in US evaluated 1826 patients and observed fewer pulmonary exacerbations in the past 2 years among patients with NTM infection than those among patients without NTM infection [28]. The discrepancy in these results may be due to the heterogeneity of characteristics of the study population, such as comorbidities, severity of bronchiectasis, and combination with P. aeruginosa infection. NTM disease is a chronic infection, as studies have demonstrated that 41.2%–55.3% of patients with nodular bronchiectasis and NTM pulmonary disease show worsening HRCT findings for a follow-up of 10 years [45, 46]. Our data also suggested NTM infection is a risk factor for the aggravation of bronchiectasis. However, the impact of NTM infection on the prognosis of patients with bronchiectasis is worthy of a thorough investigation in the future.

In this study, the most commonly isolated NTM in patients with bronchiectasis was MAC, and the least commonly isolated NTM was M. abscessus/M. chelonae, which was consistent with previous studies [9, 47‐49]. In general, the species of NTM isolated from the lower respiratory tract differ according to regions and countries. For instance, the primary bacterium causing NTM disease was the M. abscessus branch complex in Guangzhou [50] and the MAC in Beijing [22, 51]. In the present study population, the primary bacterium causing NTM disease was the MAC, which might because most patients were from Beijing. Although MAC has been predominantly isolated in most countries from pulmonary samples, M. abscessus/M. chelonae was found to be the predominant pathogenic species in Singapore [42]. Furthermore, M. xenopi was the most frequently isolated species, followed by MAC, in Southern Europe [52]. The prevalence of NTM diseases was 23.3%, which is higher than that reported by a meta-analysis (9.3%) [53]. This might be because the patients included in this study were the refractory patients nationally, who were difficult to manage than the general bronchiectasis population in Mainland China, and we used strict criteria for the diagnosis. The specimens used in this study for mycobacterial examination were BALF or lung tissue, and the proportion of BALF specimens were similar between patients with and without NTM pulmonary disease,which might largely improve the sensitivity and accuracy of diagnosis.

Our study has some limitations. First, it was a single-center study conducted on a small number of participants, which may limit the generalizability of our conclusion. However, the patients were from 19 provinces of China. Second, the residual confounders such as the treatment of bronchiectasis and NTM infection cannot be excluded. Third, because of the cross-sectional design of this study, it is difficult to reach a causal conclusion. We collected numerous clinical data and characteristics of patients with bronchiectasis in the present study to systematically evaluate the prevalence, clinical characteristics, and treatment status of patients with NTM pulmonary disease. Nevertheless, due to the study limitations, further well-designed prospective studies with a large sample size are required to further determine the impact of NTM pulmonary disease on the severity of the disease and the prognosis of patients with bronchiectasis.

In the present study patient population, the prevalence of NTM pulmonary disease among those with bronchiectasis was 23.3%, and the majority of patients (72.3%) were initiated on standard anti-NTM treatment. Nodular bronchiectasis was identified as the primary feature on the HRCT images of patients with bronchiectasis with NTM pulmonary disease. Chest HRCT scans revealed that three and more abnormal imaging features (consolidation/infiltration, nodules, tree-in-buds, and cavity) or bronchiectasis main lesions in the middle or lingual lobe were independently associated with NTM pulmonary disease. Our findings suggest that it is necessary to clearly consider the presence of NTM pulmonary disease and better management strategies in patients with bronchiectasis.